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Database: OMIM
Entry: 150330
LinkDB: 150330
MIM Entry: 150330
Title:
  *150330 LAMIN A/C; LMNA
  ;;LAMIN A;;
  LAMIN C; LMNC
  PRELAMIN A, INCLUDED
Text:
  
  DESCRIPTION
  
  The LMNA gene encodes lamin A and lamin C. Lamins are structural protein
  components of the nuclear lamina, a protein network underlying the inner
  nuclear membrane that determines nuclear shape and size. The lamins
  constitute a class of intermediate filaments. Three types of lamins, A,
  B (see LMNB1; 150340), and C, have been described in mammalian cells
  (Fisher et al., 1986).
  
  CLONING
  
  By screening human fibroblast and hepatoma cDNA libraries, Fisher et al.
  (1986) isolated cDNAs corresponding to lamin A and lamin C. The lamin A
  and C proteins are predicted to have molecular masses of 74 kD and 65
  kD, respectively. Fisher et al. (1986) and McKeon et al. (1986) found
  that the deduced amino acid sequences from cDNA clones of human lamin A
  and C are identical for the first 566 amino acids, but that lamin A
  contains an extra 98 amino acids (corresponding to approximately 9 kD)
  at the C terminus. Lamin C has 6 unique C-terminal amino acids. Both
  lamins A and C contain a 360-residue alpha-helical domain with homology
  to a corresponding alpha-helical rod domain that is the structural
  hallmark of all intermediate filament proteins. Fisher et al. (1986) and
  McKeon et al. (1986) concluded that lamin A and lamin C arise by
  alternative splicing from the same gene.
  
  Guilly et al. (1987) detected a 3-kb lamin A mRNA and a 2.1-kb lamin C
  mRNA in epithelial HeLa cells, but not in T lymphoblasts. Lamin B was
  the only lamin present in T lymphoblasts. Guilly et al. (1987) noted
  that the transport of newly synthesized proteins from the cytoplasm into
  the nucleus differs from the transport of proteins into other
  organelles, such as mitochondria, in that sequences are not cleaved and
  remain a permanent feature of the mature polypeptide. Lamin A appears to
  be an exception to this rule.
  
  Weber et al. (1989) showed that lamin A is synthesized as a precursor
  molecule called prelamin A. Maturation of lamin A involves the removal
  of 18 residues from the C terminus, which is accomplished by
  isoprenylation and farnesylation involving a C-terminal CAAX
  (cysteine-aliphatic-aliphatic-any amino acid) box (Sinensky et al.,
  1994).
  
  GENE STRUCTURE
  
  Lin and Worman (1993) demonstrated that the coding region of the lamin
  A/C gene spans approximately 24 kb and contains 12 exons. Alternative
  splicing within exon 10 gives rise to 2 different mRNAs that code for
  prelamin A and lamin C.
  
  MAPPING
  
  Wydner et al. (1996) mapped the LMNA gene to chromosome 1q21.2-q21.3 by
  fluorescence in situ hybridization.
  
  GENE FUNCTION
  
  Lloyd et al. (2002) identified proteins interacting with the C-terminal
  domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a
  yeast 2-hybrid interaction screen. Using this approach, the adipocyte
  differentiation factor SREBP1 (184756) was identified as a novel lamin A
  interactor. In vitro glutathione S-transferase pull-down and in vivo
  coimmunoprecipitation studies confirmed an interaction between lamin A
  and both SREBP1a and 1c. A binding site for lamin A was identified in
  the N-terminal transcription factor domain of SREBP1, between residues
  227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by
  FPLD mutations. The authors speculated that fat loss seen in
  laminopathies may be caused in part by reduced binding of the adipocyte
  differentiation factor SREBP1 to lamin A.
  
  Favreau et al. (2004) analyzed myoblast-to-myotube differentiation in a
  mouse myogenic cell line overexpressing wildtype or mutant human lamin
  A. In contrast to clones overexpressing wildtype lamin A, those
  expressing lamin A with the R453W mutation (150330.0002) differentiated
  poorly or not at all, did not exit the cell cycle properly, and were
  extensively committed to apoptosis. Clones expressing the R482W mutation
  (150330.0011) differentiated normally. Favreau et al. (2004) concluded
  that lamin A mutated at arginine-453 fails to build a functional
  scaffold and/or fails to maintain the chromatin compartmentation
  required for differentiation of myoblasts into myocytes.
  
  Using a novel technique to measure nuclear deformation in response to
  biaxial strain applied to cells, Lammerding et al. (2004) found that
  Lmna -/- cells showed increased nuclear deformation, defective
  mechanotransduction, and impaired viability under mechanical strain
  compared to wildtype cells. In addition, activity of nuclear
  factor-kappa-B (NFKB; 164011), a mechanical stress-responsive
  transcription factor that can act as an antiapoptotic signal, was
  impaired in the Lmna -/- cells. The findings suggested that lamin A/C
  deficiency is associated with both defective nuclear mechanics and
  impaired transcriptional activation.
  
  Broers et al. (2004) used a cell compression device to compare wildtype
  and Lmna-knockout mouse embryonic fibroblasts, and found that Lmna-null
  cells showed significantly decreased mechanical stiffness and
  significantly lower bursting force. Partial rescue of the phenotype by
  transfection with either lamin A or lamin C prevented gross nuclear
  disruption, but was unable to fully restore mechanical stiffness.
  Confocal microscopy revealed that the nuclei of Lmna-null cells
  exhibited an isotropic deformation upon indentation, despite an
  anisotropic deformation of the cell as a whole. This nuclear behavior
  suggested a loss of interaction of the disturbed nucleus with the
  surrounding cytoskeleton. Actin-(102610), vimentin-(193060), and
  tubulin-(191110) based filaments showed disturbed interaction in
  Lmna-null cells. Broers et al. (2004) suggested that in addition to the
  loss of nuclear stiffness, the loss of a physical interaction between
  nuclear structures (i.e., lamins) and the cytoskeleton may cause more
  general cellular weakness; they proposed a potential key function for
  lamins in maintaining cellular tensegrity.
  
  Van Berlo et al. (2005) showed that A-type lamins were essential for the
  inhibition of fibroblast proliferation by TGF-beta-1 (190180).
  TGF-beta-1 dephosphorylated retinoblastoma protein (RB1; 180200) through
  protein phosphatase 2A (PPP2CA; 176915), both of which were associated
  with lamin A/C. In addition, lamin A/C modulated the effect of
  TGF-beta-1 on collagen production, a marker of mesenchymal
  differentiation. Van Berlo et al. (2005) proposed a role for lamin A/C
  in control of gene activity downstream of TGF-beta-1, via nuclear
  phosphatases such as PPP2CA.
  
  Capanni et al. (2005) showed that the lamin A precursor was specifically
  accumulated in lipodystrophy cells. Pre-lamin A was located at the
  nuclear envelope and colocalized with SREBP1 Binding of SREBP1 to the
  lamin A precursor was detected in patient fibroblasts, as well as in
  control fibroblasts, forced to accumulate pre-lamin A by farnesylation
  inhibitors. In contrast, SREBP1 did not interact in vivo with mature
  lamin A or C in cultured fibroblasts. Inhibition of lamin A precursor
  processing in 3T3-L1 preadipocytes resulted in sequestration of SREBP1
  at the nuclear rim, thus decreasing the pool of active SREBP1 that
  normally activates PPAR-gamma (601487) and causing impairment of
  preadipocyte differentiation. This defect could be rescued by treatment
  with troglitazone, a known PPAR-gamma ligand activating the adipogenic
  program.
  
  Scaffidi and Misteli (2006) showed that the same molecular mechanism
  responsible for Hutchinson-Gilford progeria syndrome (HGPS; 176670) is
  active in healthy cells. Cell nuclei from old individuals acquire
  defects similar to those of HGPS patient cells, including changes in
  histone modifications and increased DNA damage. Age-related nuclear
  defects are caused by sporadic use, in healthy individuals, of the same
  cryptic splice site in lamin A whose constitutive activation causes
  HGPS. Inhibition of this splice site reverses the nuclear defects
  associated with aging. Scaffidi and Misteli (2006) concluded that their
  observations implicate lamin A in physiologic aging.
  
  Human immunodeficiency virus (HIV)-1 (see 609423) protease inhibitors
  (PIs) targeting the viral aspartyl protease are a cornerstone of
  treatment for HIV infection and disease, but they are associated with
  lipodystrophy and other side effects. Coffinier et al. (2007) found that
  treatment of human and mouse fibroblasts with HIV-PIs caused an
  accumulation of prelamin A. The prelamin A in HIV-PI-treated fibroblasts
  migrated more rapidly than nonfarnesylated prelamin A, comigrating with
  the farnesylated form found in ZMPSTE24 (606480)-deficient fibroblasts.
  HIV-PI-treated heterozygous ZMPSTE24 fibroblasts exhibited an
  exaggerated accumulation of farnesyl-prelamin A. Western blot and
  enzymatic analysis showed that HIV-PIs inhibited ZMPSTE24 activity and
  endoproteolytic processing of a GFP-prelamin A fusion protein, but they
  did not affect farnesylation of HDJ2 (DNAJA1; 602837) or activity of
  farnesyltransferase (see 134635), ICMT (605851), and RCE1 (605385) in
  vitro. Coffinier et al. (2007) concluded that HIV-PIs inhibit ZMPSTE24,
  leading to an accumulation of farnesyl-prelamin A, possibly explaining
  HIV-PI side effects.
  
  The nuclear envelope LINC complex, which is formed by SUN (e.g., SUN1;
  607723) and nesprin (e.g., SYNE1; 608441) proteins, provides a direct
  connection between the nuclear lamina and the cytoskeleton. Haque et al.
  (2010) stated that SUN1 and SUN2 interact with LMNA and that LMNA is
  required for the nuclear envelope localization of SUN2, but not SUN1.
  They found that LMNA mutations associated with Emery-Dreifuss muscular
  dystrophy (EDMD1; 310300) and HGPS disrupted interaction of LMNA with
  mouse Sun1 and human SUN2. Nuclear localization of SUN1 and SUN2 was not
  impaired in EDMD1 or HGPS cell lines. Expression of SUN1, but not SUN2,
  at the nuclear envelope was enhanced in some HGPS cells, likely due to
  increased interaction of SUN1 with accumulated prelamin A. Haque et al.
  (2010) proposed that different perturbations in LMNA-SUN protein
  interactions may underlie the opposing effects of EDMD and HGPS
  mutations on nuclear and cellular mechanics.
  
  MOLECULAR GENETICS
  
  Mutations in the LMNA gene cause a wide range of human diseases. Since
  more than 10 different clinical syndromes have been attributed to LMNA
  mutations, many of which show overlapping features, attempts at broad
  classification have been proposed. Worman and Bonne (2007) suggested
  that the disorders may be classified into 4 major types: diseases of
  striated and cardiac muscle; lipodystrophy syndromes; peripheral
  neuropathy; and premature aging. Benedetti et al. (2007) suggested 2
  main groups: (1) neuromuscular and cardiac disorders, and (2)
  lipodystrophy and premature aging disorders. The phenotypic
  heterogeneity of diseases resulting from a mutation in a single gene can
  be explained by the numerous roles of the nuclear lamina, including
  maintenance of nuclear shape and structure, as well as functional roles
  in transcriptional regulation and heterochromatin organization (review
  by Capell and Collins, 2006).
  
  Genschel and Schmidt (2000) compiled a list of 41 known mutations,
  predominantly missense, in the LMNA gene. Twenty-three different
  mutations had been shown to cause autosomal dominant Emery-Dreifuss
  muscular dystrophy (EDMD2; 181350). Three mutations had been reported to
  cause autosomal dominant limb-girdle muscular dystrophy (LGMD1B;
  159001), 8 mutations were known to result in dilated cardiomyopathy
  (CMD1A; 115200), and 7 mutations were reported to cause familial partial
  lipodystrophy (FPLD2; 151660). In addition, 1 mutation in LMNA (H222Y;
  150330.0014) appeared to be responsible for an autosomal recessive,
  atypical form of Emery-Dreifuss muscular dystrophy (EDMD3; see 181350).
  
  - Muscular Dystrophies 
  
  In 5 families with autosomal dominant Emery-Dreifuss muscular dystrophy
  (EDMD2; 181350), Bonne et al. (1999) identified 4 mutations in the LMNA
  gene (150330.0001-150330.0004) that cosegregated with the disease
  phenotype. These findings represented the first identification of
  mutations in a component of the nuclear lamina as a cause of an
  inherited muscle disorder. The authors noted that lamins interact with
  integral proteins of the inner nuclear membrane, including emerin
  (300384), which is mutated in the X-linked form of Emery-Dreifuss
  muscular dystrophy (EDMD1; 310300).
  
  Raffaele di Barletta et al. (2000) showed that heterozygous mutations in
  LMNA may cause diverse phenotypes ranging from typical EDMD to no
  phenotypic effect. LMNA mutations in patients with autosomal dominant
  EDMD occur in the tail and in the 2A rod domain of the protein,
  suggesting that unique interactions between lamin A/C and other nuclear
  components have an important role in cardiac and skeletal muscle
  function. They identified a homozygous LMNA mutation (H222Y;
  150330.0014) in 1 patient born of consanguineous unaffected parents,
  consistent with autosomal recessive inheritance and a severe atypical
  phenotype lacking cardiac features.
  
  Limb-girdle muscular dystrophy type 1B (LGMD1B; 159001) is an autosomal
  dominant, slowly progressive limb-girdle muscular dystrophy with
  age-related atrioventricular cardiac conduction disturbances and the
  absence of early contractures. Muchir et al. (2000) found mutations in
  the LMNA gene in 3 LGMD1B families: a missense mutation (150330.0017), a
  deletion of a codon (150330.0018), and a splice donor site mutation
  (150330.0019). The 3 mutations were identified in all affected members
  of the corresponding families and were absent in 100 unrelated control
  subjects.
  
  Quijano-Roy et al. (2008) described a form of congenital muscular
  dystrophy (MDC) with onset in the first year of life in 15 children
  resulting from de novo heterozygous mutations in the LMNA gene (see,
  e.g., 150330.0047-150330.0049). Three patients had severe early-onset
  disease, with decreased fetal movements in utero, no motor development,
  severe hypotonia, diffuse limb and axial muscle weakness and atrophy,
  and talipes foot deformities. The remaining 12 children initially
  acquired head and trunk control and independent ambulation, but most
  lost head control due to neck extensor weakness, a phenotype consistent
  with 'dropped head syndrome.' Ten children required ventilatory support.
  Cardiac arrhythmias were observed in 4 of the oldest patients, but were
  symptomatic only in 1. Quijano-Roy et al. (2008) concluded that the
  identified LMNA mutations appeared to correlate with a relatively severe
  phenotype, broadening the spectrum of laminopathies. The authors
  suggested that this group of patients may define a new disease entity,
  which they designated LMNA-related congenital muscular dystrophy
  (613205).
  
  Benedetti et al. (2007) reported 27 individuals with mutations in the
  LMNA gene resulting in a wide range of neuromuscular disorders.
  Phenotypic analysis yielded 2 broad groups of patients. One group
  included patients with childhood onset who had skeletal muscle
  involvement with predominant scapuloperoneal and facial weakness,
  consistent with EDMD or congenital muscular dystrophy. The second group
  included patients with later or adult onset who had cardiac disorders or
  a limb-girdle myopathy, consistent with LGMD1B. Those in the group with
  early onset tended to have missense mutations, whereas those in the
  group with adult onset tended to have truncating mutations. Analysis of
  the variants showed that those associated with early-onset phenotypes
  were primarily found in the Ig-like domain and in coil 2A, which may
  interfere with binding to specific ligands. Those associated with later
  onset were mostly located in the rod domain and in coil 2B, which was
  predicted to affect the surface of lamin A/C dimers and lead to impaired
  filament assembly. Benedetti et al. (2007) speculated that there may be
  2 different pathogenetic mechanisms associated with neuromuscular
  LMNA-related disorders: late-onset phenotypes may arise through loss of
  LMNA function secondary to haploinsufficiency, whereas dominant-negative
  or toxic gain-of-function mechanisms may underlie the more severe early
  phenotypes.
  
  - Dilated Cardiomyopathy and Cardiac Conduction Defects
  
  Fatkin et al. (1999) studied the LMNA gene in 11 families with autosomal
  dominant dilated cardiomyopathy and conduction system disease (CMD1A;
  115200) linked to a region on chromosome 1 overlapping that of the LMNA
  gene. They identified 5 novel missense mutations
  (150330.0004-150330.0009): 4 in the alpha-helical rod domain of lamin A,
  and 1 in the tail domain of lamin C. No family members with mutations
  had joint contractures or skeletal myopathy characteristic of autosomal
  dominant Emery-Dreifuss muscular dystrophy. Furthermore, serum creatine
  kinase levels were normal in family members with mutations of the lamin
  A rod domain, but mildly elevated in some family members with a defect
  in the lamin C tail domain. The authors noted that mutations in the rod
  domain of the protein led to dilated cardiomyopathy, whereas mutations
  in the head or tail domain caused Emery-Dreifuss muscular dystrophy.
  
  Van der Kooi et al. (2002) reported a sporadic patient and 2 unrelated
  families with mutations in the LMNA gene who presented with varying
  degrees and combinations of muscular dystrophy, partial lipodystrophy,
  and cardiomyopathy with conduction defects, presumably due to single
  mutations (see 150330.0003 and 150330.0005).
  
  Sebillon et al. (2003) screened the coding sequence of LMNA in DNA
  samples from 66 index cases of dilated cardiomyopathy with or without
  associated features. They identified a glu161-to-lys mutation (E161K;
  150330.0028) in a family with early-onset atrial fibrillation preceding
  or coexisting with dilated cardiomyopathy, the previously described
  R377H mutation (150330.0017) in the family with quadriceps myopathy
  associated with dilated cardiomyopathy previously reported by Charniot
  et al. (2003), and a 28insA mutation (150330.0029) leading to a
  premature stop codon in a third family with dilated cardiomyopathy with
  conduction defects. No mutation in LMNA was found in cases with isolated
  dilated cardiomyopathy.
  
  Meune et al. (2006) investigated the efficacy of implantable
  cardioverter-defibrillators (ICDs) in the primary prevention of sudden
  death in patients with cardiomyopathy due to lamin A/C gene mutations.
  Patients referred for permanent cardiac pacing were systematically
  offered the implantation of an ICD. The patients were enrolled solely on
  the basis of the presence of lamin A/C mutations associated with cardiac
  conduction defects. Indications for pacemaker implantation were
  progressive conduction block and sinus block. In all, 19 patients were
  treated. Meune et al. (2006) concluded that ICD implantation in patients
  with lamin A/C mutations who are in need of a pacemaker is effective in
  treating possibly lethal tachyarrhythmias, and that implantation of an
  ICD, rather than a pacemaker, should be considered for such patients.
  
  Taylor et al. (2003) screened the LMNA gene in 40 families and 9
  sporadic patients with CMD with or without muscular dystrophy and
  identified mutations in 3 families (see, e.g., 150330.0017) and 1
  sporadic patient (S573L; 150330.0041). All mutations involved a
  conserved residue, cosegregated with the disease within the families,
  and were not found in 300 control chromosomes. LMNA mutation carriers
  had a severe and progressive form of CMD with significantly poorer
  cumulative survival compared to noncarrier CMD patients.
  
  - Dilated Cardiomyopathy and Hypergonadotropic Hypogonadism
  
  In a 17-year-old Caucasian female with premature ovarian failure and
  dilated cardiomyopathy, who had features consistent with atypical Werner
  syndrome (see 277700) but who was negative for mutation in the RECQL2
  gene (604611), Nguyen et al. (2007) identified heterozygosity for a
  missense mutation in the LMNA gene (L59R; 150330.0052). The authors
  suggested the diagnosis of a laminopathy, most likely an atypical form
  of mandibuloacral dysplasia (see 248370).
  
  In a 15-year-old Caucasian girl with premature ovarian failure and
  dilated cardiomyopathy, McPherson et al. (2009) identified
  heterozygosity for the L59R mutation in the LMNA gene. McPherson et al.
  (2009) noted phenotypic similarities between this patient and the
  patient previously reported by Nguyen et al. (2007), who carried the
  same mutation, as well as a patient originally described by Chen et al.
  (2003) with an adjacent A57P mutation in LMNA (150330.0030). Features
  common to these 3 patients included premature ovarian failure, dilated
  cardiomyopathy, lipodystrophy, and progressive facial and skeletal
  changes involving micrognathia and sloping shoulders, but not
  acroosteolysis. Although the appearance of these patients was somewhat
  progeroid, none had severe growth failure, alopecia, or rapidly
  progressive atherosclerosis, and McPherson et al. (2009) suggested that
  the phenotype represents a distinct laminopathy involving dilated
  cardiomyopathy and hypergonadotropic hypogonadism (212112).
  
  - Lipodystrophy Disorders
  
  Patients with Dunnigan-type familial partial lipodystrophy, or partial
  lipodystrophy type 2 (FPLD2; 151660), are born with normal fat
  distribution, but after puberty experience regional and progressive
  adipocyte degeneration, often associated with profound insulin
  resistance and diabetes. Cao and Hegele (2000) hypothesized that the
  analogy between the regional muscle wasting in autosomal dominant
  Emery-Dreifuss muscular dystrophy and the regional adipocyte
  degeneration in FPLD, in addition to the chromosomal localization of the
  FPLD2 locus on 1q21-q22, made LMNA a good candidate gene for FPLD2.
  Studies of 5 Canadian probands with familial partial lipodystrophy of
  Dunnigan type indicated that each had a novel missense mutation (R482Q;
  150330.0010) that cosegregated with the lipodystrophy phenotype and was
  absent from 2,000 normal alleles.
  
  Shackleton et al. (2000) identified 5 different missense mutations in
  the LMNA gene (see, e.g., 150330.0010-150330.0012) among 10 kindreds and
  3 individuals with partial lipodystrophy. All of the mutations occurred
  in exon 8, which the authors noted is within the C-terminal globular
  domain of lamin A/C. Flier (2000) commented on the significance of LMNA
  mutations in partial lipodystrophy.
  
  Vantyghem et al. (2004) characterized the neuromuscular and cardiac
  phenotypes of FPLD patients bearing the heterozygous R482W mutation.
  Fourteen patients from 2 unrelated families, including 10 affected
  subjects, were studied. Clinical and histologic examination showed an
  incapacitating, progressive limb-girdle muscular dystrophy in a
  42-year-old woman that had been present since childhood, associated with
  a typical postpubertal FPLD phenotype. Six of 8 adults presented the
  association of calf hypertrophy, perihumeral muscular atrophy, and a
  rolling gait due to proximal lower limb weakness. Muscular histology was
  compatible with muscular dystrophy in one of them and/or showed a
  nonspecific excess of lipid droplets (in 3 cases). Cardiac septal
  hypertrophy and atherosclerosis were frequent in FPLD patients. In
  addition, a 24-year-old FPLD patient had a symptomatic second-degree
  atrioventricular block. Vantyghem et al. (2004) concluded that most
  lipodystrophic patients affected by the FPLD-linked R482W mutation show
  muscular and cardiac abnormalities.
  
  Mandibuloacral dysplasia (see 248370) is a rare autosomal recessive
  disorder characterized by postnatal growth retardation, craniofacial
  anomalies, skeletal malformations, and mottled cutaneous pigmentation.
  Patients with MAD frequently have partial lipodystrophy and insulin
  resistance, which are features seen in FPLD. In all affected members of
  5 consanguineous Italian families with MAD, Novelli et al. (2002)
  identified a homozygous missense mutation (R527H; 150330.0021) in the
  LMNA gene. Patient skin fibroblasts showed nuclei that presented
  abnormal lamin A/C distribution and a dysmorphic envelope, demonstrating
  the pathogenic effect of the mutation.
  
  In affected members of a consanguineous family from north India,
  Plasilova et al. (2004) identified a homozygous missense mutation in the
  LMNA gene (150330.0033). The extent of skeletal lesions in this family
  were consistent with MAD, but affected individuals also had classic
  features of progeria. Plasilova et al. (2004) suggested that autosomal
  recessive HGPS and mandibuloacral dysplasia may represent a single
  disorder with varying degrees of disease severity.
  
  Decaudain et al. (2007) identified changes in codon 482 of the LMNA gene
  (see, e.g., R482Q 150330.0010 and R482W; 150330.0011) in 17 of 277
  unrelated adults investigated for lipodystrophy and/or insulin
  resistance. All 17 had classic features of FPLD2. Ten additional
  patients who fulfilled the International Diabetes Federation diagnostic
  criteria for metabolic syndrome were found to have heterozygous LMNA
  mutations that were not in codon 482, but affected all 3 domains of the
  protein, the N terminal, central rod domain, and C terminal globulin
  domain (see, e.g., R399C; 150330.0043). Because the phenotype of these
  patients was not typical of FPLD2, the diagnosis of laminopathy was
  delayed. Although lipodystrophy was less severe than in typical FPLD2,
  common features included calf hypertrophy, myalgia, and muscle cramps or
  weakness. Two patients had cardiac conduction disturbances. Metabolic
  alterations were prominent, especially insulin resistance and
  hypertriglyceridemia.
  
  - Charcot-Marie-Tooth Disease Type 2B1
  
  In affected members of inbred Algerian families with an axonal form of
  Charcot-Marie-Tooth disease linked to chromosome 1q21.2-q21.3 (CMT2B1;
  605588), De Sandre-Giovannoli et al. (2002) found a shared common
  homozygous ancestral haplotype that was suggestive of a founder mutation
  and identified a unique mutation in the LMNA rod domain (R298C;
  150330.0020). Ultrastructural studies of sciatic nerves of Lmna-null
  mice showed a strong reduction of axon density, axonal enlargement, and
  the presence of nonmyelinated axons, all of which were highly similar to
  the phenotypes of human peripheral axonopathies.
  
  - Hutchinson-Gilford Progeria Syndrome and Other Premature
  Aging Syndromes
  
  Eriksson et al. (2003) identified de novo heterozygous point mutations
  in lamin A that cause Hutchinson-Gilford progeria syndrome (HGPS;
  176670). Eighteen of 20 classic cases of HGPS harbored the identical de
  novo single-base substitution resulting in a silent gly-to-gly change at
  codon 608 within exon 11 (150330.0022). This change creates an exonic
  consensus splice site and activates cryptic splicing, leading to
  deletion of 50 codons at the end of prelamin A. This prelamin A still
  retains the CAAX box but lacks the site for endoproteolytic cleavage.
  Eriksson et al. (2003) suggested that there is at least 1 site for
  phosphorylation, ser625, that is deleted in the abnormal lamin A
  protein. De Sandre-Giovannoli et al. (2003) independently identified the
  heterozygous exon 11 cryptic splice site activation mutation
  (1824C-T+1819-1968del; 150330.0022) in 2 HGPS patients. Later cellular
  studies (Capell et al., 2005; Glynn and Glover, 2005; Toth et al., 2005)
  indicated that Hutchinson-Gilford progeria syndrome results from the
  production of a truncated prelamin A, called progerin, which is
  farnesylated at its C terminus and accumulates at the nuclear envelope,
  causing misshapen nuclei (Yang et al., 2006).
  
  Werner syndrome (277700) is an autosomal recessive progeroid syndrome
  caused by mutation in the RECQL2 gene (WRN; 604611). Chen et al. (2003)
  reported that of 129 index patients referred to their international
  registry for molecular diagnosis of Werner syndrome, 26 (20%) had
  wildtype RECQL2 coding regions and were categorized as having 'atypical
  Werner syndrome' or 'non-WRN' on the basis of molecular criteria.
  Because of some phenotypic similarities between Werner syndrome and
  laminopathies including Hutchinson-Gilford progeria, Chen et al. (2003)
  sequenced all exons of the LMNA gene in these 26 individuals and found
  heterozygosity for novel missense mutations in LMNA in 4 (15%): A57P
  (150330.0030), R133L (150330.0027) in 2 persons, and L140R
  (150330.0031). Hegele (2003) stated that the clinical designation of
  Werner syndrome for each of the 4 patients of Chen et al. (2003), in
  whom mutations in the LMNA gene were found, appeared somewhat insecure.
  He noted that the comparatively young ages of onset in the patients with
  mutant LMNA would be just as consistent with late-onset
  Hutchinson-Gilford syndrome as with early-onset Werner syndrome.
  Patients with so-called atypical Werner syndrome and mutant LMNA also
  expressed components of nonprogeroid laminopathies. Hegele (2003)
  suggested that genomic DNA analysis can help draw a diagnostic line that
  clarifies potential overlap between older patients with
  Hutchinson-Gilford syndrome and younger patients with Werner syndrome,
  and that therapies may depend on precise molecular classification.
  
  McPherson et al. (2009) suggested that the patient in whom Chen et al.
  (2003) identified an A57P LMNA mutation had a distinct phenotype
  involving dilated cardiomyopathy and hypergonadotropic hypogonadism
  (212112).
  
  Csoka et al. (2004) screened 13 cell lines from atypical progeroid
  patients for mutation in the LMNA gene. They identified 3 novel
  heterozygous missense mutations in the LMNA gene in 3 patients: a
  13-year-old female with a progeroid syndrome, a 15-year-old male with a
  lipodystrophy, and a 20-year-old male with 'atypical progeria.' The
  mutations identified in the last 2 patients were the most 5-prime and
  3-prime missense mutations, respectively, in LMNA identified to that
  time.
  
  Reddel and Weiss (2004) reported that transcription efficiencies of the
  mutant and wildtype LMNA alleles were equivalent in HGPS. The mutant
  allele gave 2 types of transcripts that encoded truncated and normal
  lamin A. Abnormally spliced progerin transcript constituted the majority
  (84.5%) of the total steady-state mRNA derived from the mutant allele.
  The abnormally spliced progerin transcript was a minority (40%) of all
  lamin A transcripts obtained from both alleles. Reddel and Weiss (2004)
  concluded that the mutated progerin functions as a dominant negative by
  interfering with the structure of the nuclear lamina, intranuclear
  architecture, and macromolecular interactions, which collectively would
  have a major impact on nuclear function.
  
  Fibroblasts from individuals with HGPS have severe morphologic
  abnormalities in nuclear envelope structure. Scaffidi and Misteli (2005)
  showed that the cellular disease phenotype is reversible in cells from
  individuals with HGPS. Introduction of wildtype lamin A protein did not
  rescue the cellular disease manifestations. The mutant LMNA mRNA and
  lamin A protein could be efficiently eliminated by correction of the
  aberrant splicing event using a modified oligonucleotide targeted to the
  activated cryptic splice site. Upon splicing correction, HGPS
  fibroblasts assumed normal nuclear morphology, the aberrant nuclear
  distribution and cellular levels of lamina-associated proteins were
  rescued, defects in heterochromatin-specific histone modifications were
  corrected, and proper expression of several misregulated genes was
  reestablished. The results established proof of principle for the
  correction of the premature aging phenotype in individuals with HGPS.
  
  Huang et al. (2005) designed short hairpin RNAs (shRNA) targeting
  mutated pre-spliced or mature LMNA mRNAs and expressed them in HGPS
  fibroblasts carrying the 1824C-T mutation (150330.0022). One of the
  shRNAs reduced the expression levels of mutant lamin A (so-called LA
  delta-50) to 26% or lower. The reduced expression was associated with
  amelioration of abnormal nuclear morphology, improvement of
  proliferative potential, and reduction in the numbers of senescent
  cells.
  
  Moulson et al. (2007) reported 2 unrelated patients with extremely
  severe forms of HGPS associated with unusual mutations in the LMNA gene
  (150330.0036 and 150330.0040, respectively). Both mutations resulted in
  increased use of the cryptic exon 11 donor splice site that is also
  observed with the common 1824C-T mutation (150330.0022). As a
  consequence, the ratios of mutant progerin mRNA and protein to wildtype
  were higher than in typical HGPS patients. The findings indicated that
  the level of progerin expression correlates with severity of disease.
  
  Scaffidi and Misteli (2008) found that progerin (150330.0022) expression
  in immortalized human skin fibroblasts produced several defects typical
  of HGPS. Progerin also caused the spontaneous differentiation of human
  mesenchymal stem cells (MSCs) into endothelial cells, and reduced their
  differentiation along the adipogenic lineage. Abnormal differentiation
  of MSCs appeared to be due to progerin-induced activation of major
  downstream effectors of the Notch signaling pathway, including HES1
  (139605), HES5 (607348), and HEY1 (602953). Scaffidi and Misteli (2008)
  noted that the progerin splice variant of LMNA is present at low levels
  in cells from healthy individuals and has been implicated in the normal
  aging process. They suggested that progerin-induced defects in Notch
  signaling are involved in normal aging and similarly affect adult MSCs
  and their differentiation.
  
  - Restrictive Dermopathy
  
  In 2 of 9 fetuses with restrictive dermopathy (275210), a lethal
  genodermatosis in which tautness of the skin causes fetal akinesia or
  hypokinesia deformation sequence, Navarro et al. (2004) identified
  heterozygous splicing mutations in the LMNA gene, resulting in the
  complete or partial loss of exon 11 (150330.0036 and 150330.0022,
  respectively). In the other 7 patients, they identified a heterozygous
  1-bp insertion resulting in a premature stop codon in the zinc
  metalloproteinase STE24 gene (ZMPSTE24; 606480). This gene encodes a
  metalloproteinase specifically involved in the posttranslational
  processing of lamin A precursor. In all patients carrying a ZMPSTE24
  mutation, loss of expression of lamin A as well as abnormal patterns of
  nuclear sizes and shapes and mislocalization of lamin-associated
  proteins was seen. Navarro et al. (2004) concluded that a common
  pathogenetic pathway, involving defects of the nuclear lamina and
  matrix, is involved in restrictive dermopathy.
  
  Navarro et al. (2005) described 7 previously reported patients and 3 new
  patients with restrictive dermopathy who were homozygous or compound
  heterozygous for ZMPSTE24 mutations. In all cases there was complete
  absence of both ZMPSTE24 and mature lamin A, associated with prelamin A
  accumulation. The authors concluded that restrictive dermopathy is
  either a primary or a secondary laminopathy, caused by dominant de novo
  LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations.
  The accumulation of truncated or normal length prelamin A is, therefore,
  a shared pathophysiologic feature in recessive and dominant restrictive
  dermopathy.
  
  - Heart-Hand Syndrome, Slovenian Type
  
  In a Slovenian family with heart-hand syndrome (610140), originally
  reported by Sinkovec et al. (2005), Renou et al. (2008) identified a
  splice site mutation in the LMNA gene (150330.0045) that segregated with
  disease and was not found in 100 healthy controls. Analysis of
  fibroblasts from 2 affected members of the family revealed truncated
  lamin A/C protein and nuclear envelope abnormalities, confirming the
  pathogenicity of the mutation.
  
  - Other Associations
  
  Hegele et al. (2000) identified a common single-nucleotide polymorphism
  (SNP) in LMNA, 1908C/T, which was associated with obesity-related traits
  in Canadian Oji-Cree. Hegele et al. (2001) reported association of this
  LMNA SNP with anthropometric indices in 186 nondiabetic Canadian Inuit.
  They found that physical indices of obesity, such as body mass index,
  waist circumference, waist-to-hip circumference ratio, subscapular
  skinfold thickness, and subscapular-to-triceps skinfold thickness ratio
  were each significantly higher among Inuit subjects with the LMNA 1908T
  allele than in subjects with the 1908C/1908C genotype. For each
  significantly associated obesity-related trait, the LMNA 1908C/T SNP
  genotype accounted for approximately 10 to 100% of the attributable
  variation. The results indicated that common genetic variation in LMNA
  is an important determinant of obesity-related quantitative traits.
  
  GENOTYPE/PHENOTYPE CORRELATIONS
  
  In 14 of 15 families with familial partial lipodystrophy, Speckman et
  al. (2000) identified mutations in exon 8 of the LMNA gene: 5 families
  had an R482Q mutation (150330.0010); 7 families had an R482W alteration
  (150330.0011), and 1 family had a G465D alteration (150330.0015). The
  R482Q and R482W mutations occurred on different haplotypes, indicating
  that they probably had arisen more than once. One family with an
  atypical form of familial partial lipodystrophy had an R582H mutation
  (150330.0016) in exon 11 of the LMNA gene, which the authors noted can
  affect the lamin A protein only. Speckman et al. (2000) noted that all
  mutations in Dunnigan lipodystrophy affect the globular C-terminal
  domain of the lamin A/C protein, whereas mutations responsible for
  dilated cardiomyopathy and conduction-system disease are usually
  clustered in the rod domain of the protein (Fatkin et al., 1999).
  Speckman et al. (2000) could not detect mutations in the LMNA gene in 1
  FPLD family that showed linkage to 1q21-q23.
  
  Hegele (2005) used hierarchical cluster analysis to assemble 16
  laminopathy phenotypes into 2 classes based on organ system involvement,
  and then classified 91 reported causative LMNA mutations according to
  their position upstream or downstream of the nuclear localization signal
  (NLS) sequence. Contingency analysis revealed that laminopathy class and
  LMNA mutation position were strongly correlated (p less than 0.0001),
  suggesting that laminopathy phenotype and LMNA genotype are nonrandomly
  associated.
  
  Lanktree et al. (2007) analyzed the LMNA gene in 3 unrelated patients
  with FPLD2 and identified heterozygosity for 3 different missense
  mutations, all affecting only the lamin A isoform and each changing a
  conserved residue. Two of the mutations, D230N (150330.0042) and R399C
  (150330.0043), were 5-prime to the NLS, which is not typical of LMNA
  mutations in FPLD2. The third mutation, S573L (150330.0041), had
  previously been identified in heterozygosity in a patient with dilated
  cardiomyopathy and conduction defects (CMD1A; 115200) and in
  homozygosity in a patient with arthropathy, tendinous calcinosis, and
  progeroid features (see 248370). None of the mutations were found in 200
  controls of multiple ethnicities. Because heterozygosity for an S573L
  mutation can cause cardiomyopathy without lipodystrophy or lipodystrophy
  without cardiomyopathy, Lanktree et al. (2007) suggested that additional
  factors, genetic or environmental, may contribute to the precise tissue
  involvement.
  
  ANIMAL MODEL
  
  Mounkes et al. (2003) attempted to create a mouse model for autosomal
  dominant Emery-Dreifuss muscular dystrophy (181350) by introducing a
  L530P (150330.0004) mutation in the LMNA gene. Although mice
  heterozygous for L530P did not show signs of muscular dystrophy and
  remained overtly normal up to 6 months of age, mice homozygous for the
  mutation showed phenotypes markedly reminiscent of symptoms observed in
  progeria patients. Homozygous Lmna L530P/L530P mice were
  indistinguishable from their littermates at birth, but by 4 to 6 days
  developed severe growth retardation, dying within 4 to 5 weeks.
  Homozygous mutant mice showed a slight waddling gait, suggesting
  immobility of joints. Other progeria features of these mutant mice
  included micrognathia and abnormal dentition--in approximately half of
  the mutants a gap was observed between the lower 2 incisors, which also
  appeared yellowed. Mutant mice also had loss of subcutaneous fat,
  reduced numbers of eccrine and sebaceous glands, increased collagen
  deposition in skin, and decreased hair follicle density. Mounkes et al.
  (2003) concluded that Lmna L530P/L530P mice have significant phenotypic
  overlap with Hutchinson-Gilford progeria syndrome, including nuclear
  envelope abnormalities and decreased doublet capacity and life span of
  fibroblasts.
  
  Mounkes et al. (2005) generated mice expressing the human N195K
  (150330.0007) mutation and observed characteristics consistent with
  CMD1A. Continuous electrocardiographic monitoring of cardiac activity
  demonstrated that N195K-homozygous mice died at an early age due to
  arrhythmia. Immunofluorescence and Western blot analysis showed that
  Hf1b/Sp4 (600540), connexin-40 (GJA5; 121013), and connexin-43 (GJA1;
  121014) were misexpressed and/or mislocalized in N195K-homozygous mouse
  hearts. Desmin staining revealed a loss of organization at sarcomeres
  and intercalated disks. Mounkes et al. (2005) hypothesized that
  mutations within the LMNA gene may cause cardiomyopathy by disrupting
  the internal organization of the cardiomyocyte and/or altering the
  expression of transcription factors essential to normal cardiac
  development, aging, or function.
  
  Arimura et al. (2005) created a mouse model of autosomal dominant
  Emery-Dreifuss muscular dystrophy expressing a H222P mutation in Lmna
  (150330.0014). At adulthood, male homozygous mice displayed reduced
  locomotion activity with abnormal stiff walking posture, and all died by
  9 months of age. They also developed dilated cardiomyopathy with
  hypokinesia and conduction defects. These skeletal and cardiac muscle
  features were also observed in the female homozygous mice, but with a
  later onset than in males. Histopathologic analysis of the mice revealed
  muscle degeneration with fibrosis associated with dislocation of
  heterochromatin and activation of Smad signaling in heart and skeletal
  muscles.
  
  Varga et al. (2006) created transgenic mice carrying the G608G
  (150330.0022)-mutated human LMNA gene and observed the development of a
  dramatic defect of the large arteries, consisting of progressive medial
  vascular smooth muscle cell loss and replacement with proteoglycan and
  collagen followed by vascular remodeling with calcification and
  adventitial thickening. In vivo, these arterial abnormalities were
  reflected by a blunted initial response to the vasodilator sodium
  nitroprusside, consistent with impaired vascular relaxation, and
  attenuated blood pressure recovery after infusion. Varga et al. (2006)
  noted that although G608G transgenic mice lacked the external phenotype
  seen in human progeria, they demonstrated a progressive vascular
  abnormality that closely resembled the most lethal aspect of the human
  phenotype.
  
  Frock et al. (2006) found that most cultured muscle cells from Lmna
  knockout mice exhibited impaired differentiation kinetics and reduced
  differentiation potential. Similarly, knockdown of Lmna or emerin (EMD;
  300384) expression by RNA interference in normal muscle cells impaired
  differentiation potential and reduced expression of muscle-specific
  genes, Myod (159970) and desmin (125660). To determine whether impaired
  myogenesis was linked to reduced Myod or desmin levels, Frock et al.
  (2006) individually expressed these proteins in Lmna-null myoblasts and
  found that both increased the differentiation potential of mutant
  myoblasts. Frock et al. (2006) concluded that LMNA and emerin are
  required for myogenic differentiation, at least in part, through an
  effect on expression of critical myoblast proteins.
  
  Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production
  of a truncated prelamin A, called progerin, which is farnesylated at its
  C terminus and accumulates at the nuclear envelope, causing misshapen
  nuclei (Yang et al., 2006). Farnesyltransferase inhibitors (FTIs) have
  been shown to reverse this cellular abnormality (Yang et al., 2005; Toth
  et al., 2005; Capell et al., 2005; Mallampalli et al., 2005). Yang et
  al. (2006) generated mice with a targeted HGPS mutation (Lmna HG/+) and
  observed phenotypes similar to those in human HGPS patients, including
  retarded growth, reduced amounts of adipose tissue, micrognathia,
  osteoporosis, and osteolytic lesions in bone, which caused spontaneous
  rib fractures in the mutant mice. Treatment with an FTI increased
  adipose tissue mass, improved body weight curves, reduced the number of
  rib fractures, and improved bone mineralization and bone cortical
  thickness.
  
  Yang et al. (2008) created knockin mice expressing a nonfarnesylatable
  form of progerin. Knockin mice developed the same disease phenotype as
  mice expressing farnesylated progerin, although the phenotype was
  milder, and embryonic fibroblasts derived from these mice contained
  fewer misshapen nuclei. The steady-state level of nonfarnesylated
  progerin, but not mRNA, was lower in cultured fibroblasts and whole
  tissues, suggesting that the absence of farnesylation may accelerate
  progerin turnover.
  
  In a mouse model of EDMD carrying an H222P mutation in the Lmna gene
  (Arimura et al., 2005), Muchir et al. (2007) found that activation of
  MAPK (see 176948) pathways preceded clinical signs or detectable
  molecular markers of cardiomyopathy. Expression of H222P-mutant Lmna in
  heart tissue and isolated cardiomyocytes resulted in tissue-specific
  activation of MAPKs and downstream target genes. The results suggested
  that activation of MAPK pathways plays a role in the pathogenesis of
  cardiac disease in EDMD.
  
  Muchir et al. (2009) demonstrated abnormal activation of the
  extracellular signal-regulated kinase (ERK) branch of the
  mitogen-activated protein kinase (MAPK) signaling cascade in hearts of
  Lmna H222P knockin mice, a model of autosomal Emery-Dreifuss muscular
  dystrophy. Systemic treatment of Lmna H222P/H222P mice that developed
  cardiomyopathy with PD98059, an inhibitor of ERK activation, inhibited
  ERK phosphorylation and blocked the activation of downstream genes in
  heart. It also blocked increased expression of RNAs encoding natriuretic
  peptide precursors and proteins involved in sarcomere organization that
  occurred in placebo-treated mice. Histologic analysis and
  echocardiography demonstrated that treatment with PD98059 delayed the
  development of left ventricular dilatation. PD98059-treated Lmna
  H222P/H222P mice had normal cardiac ejection fractions assessed by
  echocardiography, whereas placebo-treated mice had a 30% decrease. The
  authors emphasized the role of ERK activation in the development of
  cardiomyopathy caused by LMNA mutations, and provided further proof of
  principle for ERK inhibition as a therapeutic option to prevent or delay
  heart failure in humans with Emery-Dreifuss muscular dystrophy and
  related disorders caused by mutations in LMNA.
  
Allelic Variants:
  .0001
  EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
  LMNA, GLN6TER 
  
  In a family with autosomal dominant Emery-Dreifuss muscular dystrophy
  (181350), Bonne et al. (1999) identified a C-to-T transition in exon 1
  of the LMNA gene that changed glutamine-6 (CAG) to a stop codon (TAG).
  
  .0002
  EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
  LMNA, ARG453TRP 
  
  In a family with autosomal dominant Emery-Dreifuss muscular dystrophy
  (181350), Bonne et al. (1999) demonstrated a C-to-T transition in exon 7
  of the LMNA gene, resulting in an arg453-to-trp (R453W) substitution.
  
  .0003
  EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2, INCLUDED
  LMNA, ARG527PRO
  
  In 2 families with autosomal dominant Emery-Dreifuss muscular dystrophy
  (181350), Bonne et al. (1999) found a G-to-C transversion in the LMNA
  gene which, resulting in an arg527-to-pro (R527P) substitution. The
  mutation, found in heterozygous state, was demonstrated to be de novo in
  both families.
  
  Van der Kooi et al. (2002) reported a woman with limb-girdle muscle
  weakness, spinal rigidity, contractures, elevated creatine kinase,
  cardiac conduction abnormalities (atrial fibrillation), partial
  lipodystrophy (151660), and increased serum triglycerides who had the
  R527P mutation. Van der Kooi et al. (2002) also reported a family with
  the R527P mutation in which the proband, her father, and her son all
  presented with varying degrees of EDMD, lipodystrophy, and cardiac
  conduction abnormalities.
  
  Makri et al. (2009) reported 2 sisters with early-onset autosomal
  dominant muscular dystrophy most consistent with EDMD. Because the girls
  were born of consanguineous Algerian parents, they were at first thought
  to have an autosomal recessive congenital muscular dystrophy. However,
  genetic analysis identified a heterozygous R527P mutation in the LMNA
  gene in both patients that was not present in either unaffected parent.
  The results were consistent with germline mosaicism or a recurrent de
  novo event. The older sib had a difficult birth and showed congenital
  hypotonia, diffuse weakness, and mild initial respiratory and feeding
  difficulties. She sat unsupported at age 2 years and walked
  independently from age 4 years with frequent falls and a waddling gait.
  At 13 years she had a high-arched palate, moderate limb hypotonia, and
  weakness of the pelvic muscles. There was proximal limb wasting,
  moderate cervical, elbow, and ankle contractures, pes cavus, spinal
  rigidity, and lordosis/scoliosis. Her sister had mild hypotonia in early
  infancy, walked without support at 24 months, and showed proximal muscle
  weakness. There were mild contractures of the elbow and ankles. At age 9
  years, she showed adiposity of the neck, trunk and abdomen, consistent
  with lipodystrophy. Brain MRI and cognition were normal in both sisters,
  and neither had cardiac involvement. Muscle biopsies showed a dystrophic
  pattern.
  
  .0004
  EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
  LMNA, LEU530PRO
  
  In a family with autosomal dominant Emery-Dreifuss muscular dystrophy
  (181350), Bonne et al. (1999) detected a heterozygous T-to-C transition
  in the LMNA gene, resulting in a leu530-to-pro (L530P) substitution.
  
  .0005
  CARDIOMYOPATHY, DILATED, 1A
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2, INCLUDED
  LMNA, ARG60GLY
  
  In a family with autosomal dominant dilated cardiomyopathy with
  conduction defects (115200), Fatkin et al. (1999) identified a 178C-G
  transversion in the LMNA gene, resulting in an arg60-to-gly (R60G)
  substitution.
  
  Van der Kooi et al. (2002) reported a woman with partial lipodystrophy
  (151660), hypertriglyceridemia, and cardiomyopathy with conduction
  defects who carried the R60G mutation. The patient's mother reportedly
  had similar manifestations. The authors noted that lipodystrophy and
  cardiac abnormalities were combined manifestations of the same mutation.
  
  .0006
  CARDIOMYOPATHY, DILATED, 1A
  LMNA, LEU85ARG
  
  In a family with autosomal dominant dilated cardiomyopathy with
  conduction defects (115200), Fatkin et al. (1999) identified a 254T-G
  transversion in the LMNA gene, resulting in a leu85-to-arg (L85R)
  substitution.
  
  .0007
  CARDIOMYOPATHY, DILATED, 1A
  LMNA, ASN195LYS
  
  In a family with autosomal dominant dilated cardiomyopathy with
  conduction defects (115200), Fatkin et al. (1999) identified a 585C-G
  transversion in the LMNA gene, resulting in an asn195-to-lys (N195K)
  substitution.
  
  .0008
  CARDIOMYOPATHY, DILATED, 1A
  LMNA, GLU203GLY
  
  In a family with autosomal dominant dilated cardiomyopathy with
  conduction defects (115200), Fatkin et al. (1999) identified a 608A-G
  transition in the LMNA gene, resulting in a glu203-to-gly (E203G)
  substitution.
  
  .0009
  CARDIOMYOPATHY, DILATED, 1A
  LMNA, ARG571SER
  
  In a family with autosomal dominant dilated cardiomyopathy and
  conduction defects (115200), Fatkin et al. (1999) identified a 1711C-A
  transversion in the LMNA gene, resulting in an arg571-to-ser (R571S)
  substitution. In this family, the C-terminal of lamin C was selectively
  affected by the mutation, and the cardiac phenotype was relatively
  milder than that associated with mutations in the rod domain of the LMNA
  gene. Furthermore, there was subclinical evidence of involvement of
  skeletal muscle. Although affected members of this family had no
  skeletal muscle symptoms, some had elevated serum creatine kinase
  levels, including 1 asymptomatic family member with the genotype
  associated with the disease. The arg571-to-ser mutation affected only
  lamin C isoforms, whereas previously described defects causing
  Emery-Dreifuss muscular dystrophy (181350) perturbed both lamin A and
  lamin C isoforms.
  
  .0010
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  LMNA, ARG482GLN
  
  In 5 probands from 5 Canadian kindreds with familial partial
  lipodystrophy of the Dunnigan type (151660), Cao and Hegele (2000)
  demonstrated heterozygosity for a G-to-A transition in exon 8 of the
  LMNA gene, predicted to result in an arg484-to-gln (R482Q) substitution.
  There were no differences in age, gender, or body mass index in
  Q482/R482 heterozygotes compared with R482/R482 homozygotes (normals)
  from these families; however, there were significantly more Q482/R482
  heterozygotes who had definite partial lipodystrophy and frank diabetes.
  Also compared with the normal homozygotes, heterozygotes had
  significantly higher serum insulin and C-peptide (see 176730) levels.
  The LMNA heterozygotes with diabetes were significantly older than
  heterozygotes without diabetes.
  
  Shackleton et al. (2000) found the R482Q mutation in a family with
  familial partial lipodystrophy. Hegele et al. (2000) analyzed the
  relationship between plasma leptin (164160) and the rare LMNA R482Q
  mutation in 23 adult familial partial lipodystrophy (FPLD) subjects
  compared with 25 adult family controls with normal LMNA in an extended
  Canadian FPLD kindred. They found that the LMNA Q482/R482 genotype was a
  significant determinant of plasma leptin, the ratio of plasma leptin to
  body mass index (BMI), plasma insulin, and plasma C peptide, but not
  BMI. Family members who were Q482/R482 heterozygotes had significantly
  lower plasma leptin and leptin:BMI ratio than unaffected R482/R482
  homozygotes. Fasting plasma concentrations of insulin and C peptide were
  both significantly higher in LMNA Q482/R482 heterozygotes than in
  R482/R482 homozygotes. Multivariate regression analysis revealed that
  the LMNA R482Q genotype accounted for 40.9%, 48.2%, 86.9%, and 81.0%,
  respectively, of the attributable variation in log leptin, leptin:BMI
  ratio, log insulin, and log C peptide. The authors concluded that a rare
  FPLD mutation in LMNA determines the plasma leptin concentration.
  
  Boguslavsky et al. (2006) found that overexpression of wildtype LMNA or
  mutant R482Q or R482W (150330.0011) in mouse 3T3-L1 preadipocytes
  prevented cellular lipid accumulation, inhibited triglyceride synthesis,
  and prevented normal differentiation into adipocytes. In contrast,
  embryonic fibroblasts from Lmna-null mice had increased levels of basal
  triglyceride synthesis and differentiated into fat-containing cells more
  readily that wildtype mouse cells. Mutations at residue 482 are not
  predicted to affect the structure of the nuclear lamina, but may change
  interactions with other proteins. The findings of this study suggested
  that mutations responsible for FPLD are gain-of-function mutations.
  Boguslavsky et al. (2006) postulated that mutations that result in gain
  of function may cause higher binding affinity to a proadipogenic
  transcription factor, thus preventing it from activating target genes;
  overexpression of the wildtype protein may result in increased numbers
  of molecules with a normal binding affinity. Overexpression of Lmna was
  associated with decreased levels of PPARG2 (601487), a nuclear hormone
  receptor transcription factor putatively involved in adipogenic
  conversion. Lmna-null cells had increased basal phosphorylation of AKT1
  (164730), a mediator of insulin signaling.
  
  .0011
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  LMNA, ARG482TRP 
  
  In 6 families and 3 isolated cases of partial lipodystrophy (151660),
  Shackleton et al. (2000) found heterozygosity for C-to-T transition in
  the LMNA gene, resulting in an arg482-to-trp (R482W) substitution. This
  is the same codon as that affected in the R482Q mutation (150330.0010).
  R482L (150330.0012) is a third mutation in the same codon causing
  partial lipodystrophy.
  
  Schmidt et al. (2001) identified a family with partial lipodystrophy
  carrying the R482W mutation in the LMNA gene. Clinically, the loss of
  subcutaneous fat and muscular hypertrophy, especially of the lower
  extremities, started as early as in childhood. Acanthosis and severe
  hypertriglyceridemia developed later in life, followed by diabetes.
  Characterization of the lipoprotein subfractions revealed that affected
  children present with hyperlipidemia. The presence and severity of
  hyperlipidemia seem to be influenced by age, apolipoprotein E genotype,
  and the coexistence of diabetes mellitus. In conclusion, dyslipidemia is
  an early and prominent feature in the presented lipodystrophic family
  carrying the R482W mutation.
  
  .0012
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  LMNA, ARG482LEU 
  
  In a family with partial lipodystrophy (151660), Shackleton et al.
  (2000) found that the affected individuals were heterozygous for a
  G-to-T transversion in the LMNA gene, resulting in an arg482-to-leu
  (R482L) substitution.
  
  .0013
  CARDIOMYOPATHY, DILATED, 1A
  EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT, INCLUDED
  LMNA, 1-BP DEL, 959T 
  
  In a large family with a severe autosomal dominant dilated
  cardiomyopathy with conduction defects (115200) in which the majority of
  affected family members showed signs of mild skeletal muscle
  involvement, Brodsky et al. (2000) demonstrated heterozygosity in
  affected members for a 1-bp deletion (del959T) deletion in exon 6 of the
  LMNA gene. One individual had a pattern of skeletal muscle involvement
  that the authors considered consistent with mild Emery-Dreifuss muscular
  dystrophy (181350).
  
  .0014
  EMERY-DREIFUSS MUSCULAR DYSTROPHY, ATYPICAL, AUTOSOMAL RECESSIVE
  LMNA, HIS222TYR 
  
  In a 40-year-old man with a severe, atypical form of EDMD (see 181350),
  Raffaele di Barletta et al. (2000) found a homozygous 664C-T transition
  in the LMNA gene, resulting in a his222-to-tyr (H222Y) amino acid
  substitution. Both parents, who were first cousins, were heterozygous
  for the mutation and were unaffected. The mutation was not found among
  200 control chromosomes. The patient was the only one with a homozygous
  LMNA mutation among a larger study of individuals with autosomal
  dominant Emery-Dreifuss muscular dystrophy.
  
  .0015
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  LMNA, GLY465ASP
  
  Speckman et al. (2000) found that 1 of 15 families with familial partial
  lipodystrophy of the Dunnigan variety (151660) harbored a gly465-to-asp
  (G465D) mutation in exon 8 of the LMNA gene.
  
  .0016
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  LMNA, ARG582HIS
  
  In a family with an atypical form of familial partial lipodystrophy
  (151660), Speckman et al. (2000) identified an arg582-to-his (R582H)
  mutation in exon 11 of the LMNA gene. In a follow-up of this same
  family, Garg et al. (2001) reported that 2 affected sisters showed less
  severe loss of subcutaneous fat from the trunk and extremities with some
  retention of fat in the gluteal region and medial parts of the proximal
  thighs compared to women with typical FPLD2. Noting that the R582H
  mutation interrupts only the lamin A protein, Garg et al. (2001)
  suggested that in typical FPLD2, interruption of both lamins A and C
  causes a more severe phenotype than that seen in atypical FPLD2, in
  which only lamin A is altered.
  
  .0017
  MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
  CARDIOMYOPATHY, DILATED, 1A, INCLUDED
  LMNA, ARG377HIS 
  
  In a family with limb-girdle muscular dystrophy type 1B (159001), Muchir
  et al. (2000) found a G-to-A transition in exon 6 of the LMNA gene,
  resulting in a substitution of histidine for arginine-377 (R377H).
  
  Taylor et al. (2003) identified heterozygosity for the R377H mutation in
  an American family of British descent with autosomal dominant dilated
  cardiomyopathy and mild limb-girdle muscular disease.
  
  Charniot et al. (2003) described a French family with autosomal dominant
  severe dilated cardiomyopathy with conduction defects or
  atrial/ventricular arrhythmias and a skeletal muscular dystrophy of the
  quadriceps muscles. Affected members were found to carry the R377H
  mutation, which was shown by transfection experiments in both muscular
  and nonmuscular cells to lead to mislocalization of both lamin and
  emerin (300384). Unlike previously reported cases of LMNA mutations
  causing dilated cardiomyopathy with neuromuscular involvement, cardiac
  involvement preceded neuromuscular disease in all affected members.
  Charniot et al. (2003) suggested that factors other than the R377H
  mutation influenced phenotypic expression in this family. Sebillon et
  al. (2003) also reported on this family.
  
  In a German woman with LGMD1B, Rudnik-Schoneborn et al. (2007)
  identified a heterozygous R377H mutation in the LMNA gene. Family
  history revealed that the patient's paternal grandmother had proximal
  muscle weakness and died from heart disease at age 52, and a paternal
  aunt had 'walking difficulties' since youth. The patient's father and 4
  cousins all had cardiac disease without muscle weakness ranging from
  nonspecific 'heart attacks' to dilated cardiomyopathy and arrhythmia.
  The only living affected cousin also carried the mutation.
  
  .0018
  MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
  LMNA, 3-BP DEL, EXON 3 
  
  In a family with limb-girdle muscular dystrophy type 1B (159001), Muchir
  et al. (2000) found a 3-bp deletion (AAG) in exon 3 of the LMNA gene,
  resulting in loss of the codon for lysine-208 (delK208).
  
  .0019
  MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
  LMNA, IVS9, G-C, +5 
  
  In a family with limb-girdle muscular dystrophy type 1B (159001), Muchir
  et al. (2000) found a G-to-C transversion in the splice donor site of
  intron 9, leading to retention of intron 9 and a frameshift at position
  536. This potentially results in a truncated protein lacking half of the
  globular tail domain of lamins A/C.
  
  .0020
  CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B1
  LMNA, ARG298CYS 
  
  De Sandre-Giovannoli et al. (2002) found a homozygous arg298-to-cys
  (R298C) mutation in the LMNA gene in affected members of Algerian
  families with CMT2B1 (605588).
  
  Ben Yaou et al. (2007) identified a homozygous R298C mutation in a
  female and 2 male affected members of an Algerian family with CMT2B1.
  The 2 males also had X-linked Emery-Dreifuss muscular dystrophy (310300)
  and a hemizygous mutation in the EMD gene (300384).
  
  .0021
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL, INCLUDED
  LMNA, ARG527HIS 
  
  In 5 consanguineous Italian families, Novelli et al. (2002) demonstrated
  that individuals with mandibuloacral dysplasia (248370) were homozygous
  for an arg527-to-his (R527H) mutation.
  
  In affected members from 2 pedigrees with MADA, Simha et al. (2003)
  identified the homozygous R527H mutation.
  
  In a Mexican American boy with MADA born of related parents, Shen et al.
  (2003) identified homozygosity for the R527H mutation. The authors noted
  that all the patients reported by Novelli et al. (2002) shared a common
  disease haplotype, but that the patients reported by Simha et al. (2003)
  and their Mexican American patient had different haplotypes, indicating
  independent origins of the mutation. The mutation is located within the
  C-terminal immunoglobulin-like domain in the center of a beta sheet on
  the domain surface of the protein.
  
  Lombardi et al. (2007) identified this mutation in compound
  heterozygosity with another missense mutation (150330.0044) in a patient
  with an apparent MADA phenotype associated with muscular hyposthenia and
  generalized hypotonia.
  
  Garavelli et al. (2009) reported 2 unrelated patients with early
  childhood onset of MADA features associated with a homozygous R527H
  mutation. One presented at age 5 years, 3 months with bulbous distal
  phalanges of fingers and was observed to have dysmorphic craniofacial
  features, lipodystrophy type A, and acroosteolysis. The second child,
  born of consanguineous Pakistani parents, presented at age 4 years, 2
  months with a round face, chubby cheeks, thin nose, lipodystrophy type
  A, and short, broad distal phalanges. Garavelli et al. (2009) emphasized
  that features of this disorder may become apparent as early as preschool
  age and that bulbous fingertips may be a clue to the diagnosis.
  
  .0022
  HUTCHINSON-GILFORD PROGERIA SYNDROME
  RESTRICTIVE DERMOPATHY, LETHAL, INCLUDED
  LMNA, GLY608GLY 
  
  In 18 of 20 patients with classic Hutchinson-Gilford progeria syndrome
  (176670), Eriksson et al. (2003) found an identical de novo 1824C-T
  transition, resulting in a silent gly-to-gly mutation at codon 608
  (G608G) within exon 11 of the LMNA gene. This substitution created an
  exonic consensus splice donor sequence and results in activation of a
  cryptic splice site and deletion of 50 codons of prelamin A. This
  mutation was not identified in any of the 16 parents available for
  testing.
  
  De Sandre-Giovannoli et al. (2003) identified the exon 11 cryptic splice
  site activation mutation (1824C-T+1819-1968del) in 2 HGPS patients.
  Immunocytochemical analyses of lymphocytes from 1 patient using specific
  antibodies directed against lamin A/C, lamin A, and lamin B1 showed that
  most cells had strikingly altered nuclear sizes and shapes, with
  envelope interruptions accompanied by chromatin extrusion. Lamin A was
  detected in 10 to 20% of HGPS lymphocytes. Only lamin C was present in
  most cells, and lamin B1 was found in the nucleoplasm, suggesting that
  it had dissociated from the nuclear envelope due to the loss of lamin A.
  Western blot analysis showed 25% of normal lamin A levels, and no
  truncated form was detected.
  
  Cao and Hegele (2003) confirmed the observations of Eriksson et al.
  (2003) using the same cell lines. They referred to this mutation as
  2036C-T.
  
  D'Apice et al. (2004) confirmed paternal age effect and demonstrated a
  paternal origin of the 2036C-T mutation in 3 families with isolated
  cases of Hutchinson-Gilford progeria.
  
  By light and electron microscopy of fibroblasts from HGPS patients
  carrying the 1824C-T mutation, Goldman et al. (2004) found significant
  changes in nuclear shape, including lobulation of the nuclear envelope,
  thickening of the nuclear lamina, loss of peripheral heterochromatin,
  and clustering of nuclear pores. These structural defects worsened as
  the HGPS cells aged in culture, and their severity correlated with an
  apparent accumulation of mutant protein, which Goldman et al. (2004)
  designated LA delta-50. Introduction of LA delta-50 into normal cells by
  transfection or protein injection induced the same changes. Goldman et
  al. (2004) hypothesized that the alterations in nuclear structure are
  due to a concentration-dependent dominant-negative effect of LA
  delta-50, leading to the disruption of lamin-related functions ranging
  from the maintenance of nuclear shape to regulation of gene expression
  and DNA replication.
  
  In an infant with restrictive dermopathy (275210), Navarro et al. (2004)
  identified the 1824C-T transition in heterozygous state.
  
  In a patient with Hutchinson-Gilford progeria, Wuyts et al. (2005)
  identified the G608G mutation. In lymphocyte DNA from the parents,
  normal wildtype alleles were observed in the father, but a low signal
  corresponding to the mutant allele was detected in the mother's DNA. A
  segregation study confirmed that the patient's mutation was transmitted
  from the mother, who showed germline and somatic mosaicism without
  manifestations of HGPS.
  
  Glynn and Glover (2005) studied the effects of farnesylation inhibition
  on nuclear phenotypes in cells expressing normal and G608G-mutant lamin
  A. Expression of a GFP-progerin fusion protein in normal fibroblasts
  caused a high incidence of nuclear abnormalities (as seen in HGPS
  fibroblasts), and resulted in abnormal nuclear localization of
  GFP-progerin in comparison with the localization pattern of GFP-lamin A.
  Expression of a GFP-lamin A fusion containing a mutation preventing the
  final cleavage step, which caused the protein to remain farnesylated,
  displayed identical localization patterns and nuclear abnormalities as
  in HGPS cells and in cells expressing GFP-progerin. Exposure to a
  farnesyltransferase inhibitor (FTI), PD169541, caused a significant
  improvement in the nuclear morphology of cells expressing GFP-progerin
  and in HGPS cells. Glynn and Glover (2005) proposed that abnormal
  farnesylation of progerin may play a role in the cellular phenotype in
  HGPS cells, and suggested that FTIs may represent a therapeutic option
  for patients with HGPS.
  
  In cells from a female patient with HGPS due to the 1824C-T mutation,
  Shumaker et al. (2006) found that the inactive X chromosome showed loss
  of histone H3 trimethylation of lys27 (H3K27me3), a marker for
  facultative heterochromatin, as well as loss of histone H3
  trimethylation of lys9 (H3K9me3), a marker of pericentric constitutive
  heterochromatin. Other alterations in epigenetic control included
  downregulation of the EZH2 methyltransferase (601573), upregulation of
  pericentric satellite III repeat transcripts, and increase in the
  trimethylation of H4K20. The epigenetic alterations were observed before
  the pathogenic changes in nuclear shape. The findings indicated that the
  mutant LMNA protein alters sites of histone methylation known to
  regulate heterochromatin and provided evidence that the rapid aging
  phenotype of HGPS reflects aspects of normal aging at the molecular
  level.
  
  Moulson et al. (2007) demonstrated that HGPS cells with the common
  1824C-T LMNA mutation produced about 37.5% of wildtype full-length
  transcript, which was higher than previous estimates (Reddel and Weiss,
  2004).
  
  Using real-time RT-PCR, Rodriguez et al. (2009) found that progerin
  transcripts were expressed in dermal fibroblasts cultured from normal
  controls, but at a level more than 160-fold lower than that detected in
  dermal fibroblasts cultured from HGPS patients. The level of progerin
  transcripts, but not of lamin A or lamin C transcripts, increased in
  late-passage cells from both normal controls and HGPS patients.
  
  .0023
  HUTCHINSON-GILFORD PROGERIA SYNDROME
  LMNA, GLY608SER 
  
  In a patient with Hutchinson-Gilford progeria syndrome (176670),
  Eriksson et al. (2003) identified a G-to-A transition in the LMNA gene
  resulting in a gly-to-ser substitution at codon 608 (G608S). This
  mutation was not identified in either parent.
  
  Cao and Hegele (2003) confirmed the observation of Eriksson et al.
  (2003) using the same cell line.
  
  .0024
  HUTCHINSON-GILFORD PROGERIA SYNDROME, ATYPICAL
  LMNA, GLU145LYS 
  
  In a patient with somewhat atypical features of progeria (176670),
  Eriksson et al. (2003) identified a glu-to-lys substitution at codon 145
  (E145K) in exon 2 of the LMNA gene. This mutation was not identified in
  either parent. Atypical clinical features, including persistence of
  coarse hair over the head, ample subcutaneous tissue over the arms and
  legs, and severe strokes beginning at age 4, may subtly distinguish this
  phenotype from classic HGPS.
  
  .0025
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL
  LMNA, ARG471CYS 
  
  In a patient with an apparently typical progeria phenotype (176670) who
  was 28 years old at the time that DNA was obtained, Cao and Hegele
  (2003) identified compound heterozygosity for 2 missense mutations in
  the LMNA gene. One mutation, arg471 to cys (R471C), resulted from a
  1623C-T transition. An arg527-to-cys (R527C) substitution (150330.0026),
  resulting from a 1791C-T transition, was found on the other allele.
  These mutations were not identified in any of 100 control chromosomes.
  Parental DNA for this patient and a clinical description of the parents
  were not available. Brown (2004) reported that both he and the patient's
  physician, Francis Collins, concluded that the patient had
  mandibuloacral dysplasia (248370).
  
  Zirn et al. (2008) reported a 7-year-old Turkish girl, born of
  consanguineous parents, who was homozygous for the R471C mutation. She
  had a phenotype most consistent with an atypical form of MADA, including
  lipodystrophy, a progeroid appearance, and congenital muscular dystrophy
  with rigid spine syndrome. These latter features were reminiscent of
  Emery-Dreifuss muscular dystrophy (181350), although there was no
  cardiac involvement. She presented at age 10 months with proximal muscle
  weakness, contractures, spinal rigidity, and a dystrophic skeletal
  muscle biopsy. Characteristic progeroid features and features of
  lipodystrophy and mandibuloacral dysplasia were noted at age 3 years and
  became more apparent with age. Zirn et al. (2008) commented on the
  severity of the phenotype and emphasized the phenotypic variability in
  patients with LMNA mutations.
  
  .0026
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
  LMNA, ARG527CYS 
  
  See 150330.0025, Cao and Hegele (2003), and Brown (2004).
  
  .0027
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  HUTCHINSON-GILFORD PROGERIA SYNDROME, CHILDHOOD-ONSET, INCLUDED
  LMNA, ARG133LEU 
  
  In a male patient whose phenotype associated generalized acquired
  lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, and
  hepatic steatosis (151660), Caux et al. (2003) found a heterozygous
  398G-T transversion in exon 2 of the LMNA gene that resulted in an
  arg-to-leu change at codon 133 (R133L) in the dimerization rod domain of
  lamins A and C. The patient also had hypertrophic cardiomyopathy with
  valvular involvement and disseminated whitish papules.
  Immunofluorescence microscopic analysis of the patient's cultured skin
  fibroblasts revealed nuclear disorganization and abnormal distribution
  of A-type lamins, similar to that observed in patients harboring other
  LMNA mutations. This observation broadened the clinical spectrum of
  laminopathies, pointing out the clinical variability of lipodystrophy
  and the possibility of hypertrophic cardiomyopathy and skin involvement.
  
  In 2 unrelated persons with a progeroid syndrome (see 176670), Chen et
  al. (2003) found heterozygosity for the R1333L mutation in the LMNA
  gene. One was a white Portuguese female who presented at the age of 9
  years with short stature. She showed scleroderma-like skin changes and
  graying/thinning of hair. Type 2 diabetes developed at the age of 23
  years. Hypogonadism, osteoporosis, and voice changes were also present.
  The other patient was an African American female in whom the diagnosis
  of a progeroid syndrome was made at the age of 18 years.
  Scleroderma-like skin, short stature, graying/thinning of hair, and type
  2 diabetes at the age of 18 years were features. The deceased father,
  paternal aunt, and paternal grandmother of this patient were also
  diagnosed with severe insulin-resistant diabetes mellitus, suggesting
  that the R133L mutation might have been paternally inherited. It is
  noteworthy that a substitution in the same codon, R133P (150330.0032),
  was reported in a 40-year-old patient with Emery-Dreifuss muscular
  dystrophy who had disease onset at age 7 years and atrial fibrillation
  at age 32 years (Brown et al., 2001). Although Chen et al. (2003)
  designated these patients as having 'atypical Werner syndrome' (277700),
  Hegele (2003) suggested that the patients more likely had late-onset
  Hutchinson-Gilford progeria syndrome.
  
  Vigouroux et al. (2003) emphasized that a striking feature in the
  patient reported by Caux et al. (2003) was muscular hypertrophy of the
  limbs, which contrasts with the muscular atrophy usually present in
  Werner syndrome. Muscular hypertrophy, along with insulin-resistant
  diabetes and hypertriglyceridemia, is more often associated with
  LMNA-linked Dunnigan lipodystrophy. Fibroblasts from their patient
  showed nuclear abnormalities identical to those described in Dunnigan
  lipodystrophy (Vigouroux et al., 2001).
  
  Jacob et al. (2005) studied the pattern of body fat distribution and
  metabolic abnormalities in the 2 patients with atypical Werner syndrome
  described by Chen et al. (2003). Patient 1, an African American female,
  had normal body fat (27%) by dual energy X-ray absorptiometry (DEXA).
  However, magnetic resonance imaging (MRI) revealed relative paucity of
  subcutaneous fat in the distal extremities, with preservation of
  subcutaneous truncal fat. She had impaired glucose tolerance and
  elevated postprandial serum insulin levels. In contrast, patient 2, a
  Caucasian female, had only 11.6% body fat as determined by DEXA and had
  generalized loss of subcutaneous and intraabdominal fat on MRI. She had
  hypertriglyceridemia and severe insulin-resistant diabetes requiring
  more than 200 U of insulin daily. Skin fibroblasts showed markedly
  abnormal nuclear morphology compared with those from patient 1. Despite
  the deranged nuclear morphology, the lamin A/C remained localized to the
  nuclear envelope, and the nuclear DNA remained within the nucleus. Jacob
  et al. (2005) concluded that atypical Werner syndrome associated with an
  R133L mutation in the LMNA gene is phenotypically heterogeneous.
  Furthermore, the severity of metabolic complications seemed to correlate
  with the extent of lipodystrophy.
  
  .0028
  CARDIOMYOPATHY, DILATED, 1A
  LMNA, GLU161LYS
  
  Sebillon et al. (2003) described a family with a history of sudden
  cardiac death, congestive heart failure, and dilated cardiomyopathy
  (115200). Five affected members had a heterozygous 481G-A transition in
  exon 2 of the LMNA gene, resulting in a glu161-to-lys (E161K) mutation.
  Dilated cardiomyopathy was present in only 2 patients, in whom onset of
  the disease was characterized by congestive heart failure and atrial
  fibrillation (at 29 and 44 years, respectively); heart transplantation
  was performed in both patients (at 34 and 51 years of age). In the 3
  other affected members, the onset of disease was also characterized by
  atrial fibrillation at 22, 49, and 63 years, but without dilated
  cardiomyopathy. A 16-year-old male and 12-year-old female were also
  heterozygous for the mutation, but had no signs or symptoms of heart
  disease. The 5 affected members were a mother and 2 daughters in 1
  branch of the family and 2 brothers in another branch. Two cardiac
  deaths were reported in the family history: sudden death at 38 years and
  congestive heart failure at 68 years. No significant atrioventricular
  block was observed in the family, except in 1 patient for whom cardiac
  pacing was necessary at 67 years of age because of sinoatrial block
  coexisting with atrial fibrillation. Sebillon et al. (2003) concluded
  that the phenotype in this family was characterized by early atrial
  fibrillation preceding or coexisting with dilated cardiomyopathy,
  without significant atrioventricular block, and without neuromuscular
  abnormalities.
  
  .0029
  CARDIOMYOPATHY, DILATED, 1A
  LMNA, 1-BP INS, 28A
  
  Sebillon et al. (2003) described a family in which 5 patients with
  dilated cardiomyopathy with conduction defects (115200) were
  heterozygous for a 1-bp insertion, 28insA, in exon 1 of the LMNA gene.
  Three additional patients were considered as phenotypically affected
  with documented dilated cardiomyopathy but were not available for DNA
  analysis. In the family history, there were 3 cardiac sudden deaths
  before 55 years of age. In the patients with dilated cardiomyopathy, 3
  had associated atrioventricular block requiring pacemaker implantation,
  1 had premature ventricular beats leading to a cardioverter
  defibrillator implantation, and 1 had a mild form of skeletal muscular
  dystrophy (mild weakness and wasting of quadriceps muscles, as well as
  myogenic abnormalities on electromyogram).
  
  .0030
  CARDIOMYOPATHY, DILATED, WITH HYPERGONADOTRIPIC HYPOGONADISM
  LMNA, ALA57PRO
  
  In an Iranian female with short stature and a progeroid syndrome (see
  176670), Chen et al. (2003) found a heterozygous de novo ala57-to-pro
  substitution (A57P) resulting from a 584G-C transversion in the LMNA
  gene. Onset occurred in her early teens, and she was 23 years old at
  diagnosis. Hypogonadism, osteoporosis, osteosclerosis of digits, and
  dilated cardiomyopathy were described. Although Chen et al. (2003)
  designated this patient as having 'atypical Werner syndrome' (277700),
  Hegele (2003) suggested that the patient more likely had late-onset
  Hutchinson-Gilford progeria syndrome.
  
  McPherson et al. (2009) suggested that the patient in whom Chen et al.
  (2003) identified an A57P LMNA mutation had a distinct phenotype
  involving dilated cardiomyopathy and hypergonadotropic hypogonadism
  (212112).
  
  .0031
  HUTCHINSON-GILFORD PROGERIA SYNDROME, CHILDHOOD-ONSET
  LMNA, LEU140ARG
  
  In a white Norwegian male with a progeroid syndrome (see 176670), Chen
  et al. (2003) found a leu140-to-arg (L140R) substitution resulting from
  an 834T-G transversion in the LMNA gene. The patient had onset at age 14
  of cataracts, scleroderma-like skin, and graying/thinning of hair, as
  well as hypogonadism, osteoporosis, soft tissue calcification, and
  premature atherosclerosis. Aortic stenosis and insufficiency were also
  present. The patient died at the age of 36 years. Although Chen et al.
  (2003) designated this patient as having 'atypical Werner syndrome'
  (277700), Hegele (2003) suggested that the patient more likely had
  late-onset Hutchinson-Gilford progeria syndrome.
  
  .0032
  EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
  LMNA, ARG133PRO
  
  In a 40-year-old patient with Emery-Dreifuss muscular dystrophy (181350)
  who had disease onset at age 7 years and atrial fibrillation at age 32
  years, Brown et al. (2001) found an arg133-to-pro (R133P) mutation in
  the LMNA gene. Chen et al. (2003) noted that the same codon is involved
  in the arg133-to-leu (150330.0027) mutation in atypical Werner syndrome.
  
  .0033
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
  LMNA, LYS542ASN
  
  In 4 affected members of a consanguineous family from north India with
  features of MADA (248370). Plasilova et al. (2004) identified a
  homozygous 1626G-C transversion in exon 10 of the LMNA gene, resulting
  in a lys542-to-asn (K542N) substitution. The parents and 1 unaffected
  daughter were heterozygous for the mutation. Patients in this family
  showed uniform skeletal malformations such as acroosteolysis of the
  digits, micrognathia, and clavicular aplasia/hypoplasia, characteristic
  of mandibuloacral dysplasia. However, the patients also had classic
  features of Hutchinson-Gilford progeria syndrome (176670). Plasilova et
  al. (2004) suggested that autosomal recessive HGPS and MADA may
  represent a single disorder with varying degrees of severity.
  
  .0034
  MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
  LMNA, SER143PHE
  
  In a young girl with congenital muscular dystrophy and progeroid
  features (see 613205), Kirschner et al. (2005) identified a 1824C-T
  transition in the LMNA gene, resulting in a de novo heterozygous
  missense mutation, ser143 to phe (S143F). The child presented during the
  first year of life with myopathy with marked axial weakness, feeding
  difficulties, poor head control and axial weakness. Progeroid features,
  including growth failure, sclerodermatous skin changes, and osteolytic
  lesions, developed later. At routine examination at age 8 years, she was
  found to have a mediolateral myocardial infarction.
  
  In cultured skin fibroblasts derived from the patient reported by
  Kirschner et al. (2005), Kandert et al. (2007) found dysmorphic nuclei
  with blebs and lobulations that accumulated progressively with cell
  passage. Immunofluorescent staining showed altered lamin A/C
  organization and aggregate formation. There was aberrant localization of
  lamin-associated proteins, particularly emerin (EMD; 300384) and
  nesprin-2 (SYNE2; 608442), which was reduced or absent from the nuclear
  envelope. However, a subset of mutant cells expressing the giant 800-kD
  isoform of SYNE2 showed a milder phenotype, suggesting that this isoform
  exerts a protective effect. Proliferating cells were observed to express
  the 800-kD SYNE2 isoform, whereas nonproliferating cells did not. In
  addition, mutant cells showed defects in the intranuclear organization
  of acetylated histones and RNA polymerase II compared to control cells.
  The findings indicated that the S143F mutant protein affects nuclear
  envelope architecture and composition, chromatin organization, gene
  expression, and transcription. The findings also implicated nesprin-2 as
  a structural reinforcer at the nuclear envelope.
  
  .0035
  MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
  LMNA, TYR259TER 
  
  In 9 affected members of Dutch family with limb-girdle muscular
  dystrophy type 1B (159001), van Engelen et al. (2005) identified a
  777T-A transversion in the LMNA gene, resulting in a tyr259-to-ter
  substitution (Y259X). The heterozygous Y259X mutation led to a classic
  LGMD1B phenotype. One infant homozygous for the mutation was born of
  consanguineous parents who were both affected, and delivered at 30
  weeks' gestational age by cesarean section because of decreasing cardiac
  rhythm. The infant died at birth from very severe generalized muscular
  dystrophy. Cultured skin fibroblasts from the infant showed complete
  absence of A-type lamins leading to disorganization of the lamina,
  alterations in the protein composition of the inner nuclear membrane,
  and decreased life span. Van Engelen et al. (2005) noted that the
  fibroblasts from this child showed remarkable similarity, in nuclear
  architectural defects and in decreased life span, to the fibroblasts of
  homozygous LMNA (L530P/L530P) mice (Mounkes et al., 2003).
  
  .0036
  RESTRICTIVE DERMOPATHY, LETHAL
  HUTCHINSON-GILFORD PROGERIA SYNDROME, INCLUDED
  LMNA, IVS11, G-A, +1 
  
  In a premature infant who died at 6 months of age due to restrictive
  dermopathy (275210), Navarro et al. (2004) identified a heterozygous
  G-to-A transition at position 1 in the intron 11 donor site of the LMNA
  gene (IVS11+1G-A), resulting in loss of exon 11 from the transcript. The
  patient expressed lamins A and C and a truncated prelamin A.
  
  In a patient with an extremely severe form of HGPS (176670), Moulson et
  al. (2007) identified a heterozygous G-to-A transition at the +1
  position of the donor splice site of intron 11 in the LMNA gene
  (1968+1G-A). RT-PCR studies showed a truncated protein product identical
  to that observed in HGPS cell lines with the common 1824C-T mutation
  (150330.0022), indicating that the new mutation resulted in the abnormal
  use of the same cryptic exon 11 splice site. The findings were in
  contrast to those reported by Navarro et al. (2004), who observed
  skipping of exon 11 with 1968+1G-A. Further quantitative studies of the
  patient's cells by Moulson et al. (2007) found a 4.5-fold increase in
  the relative ratio of mutant mRNA and protein to wildtype prelamin A
  compared to typical HGPS cells. The findings were confirmed by Western
  blot analysis and provided an explanation for the severe phenotype
  observed in this patient. He had had abnormally thick and tight skin
  observed at 11 weeks of age, and developed more typical but severe
  progeroid features over time. He died of infection at age 3.5 years.
  
  .0037
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
  LMNA, ALA529VAL
  
  In 2 unrelated Turkish patients with mandibuloacral dysplasia with type
  A lipodystrophy (248370), a 21-year-old woman previously described by
  Cogulu et al. (2003) and an 18-year-old man, Garg et al. (2005)
  identified homozygosity for a 1586C-T transition in the LMNA gene,
  resulting in an ala529-to-val (A529V) substitution. Intragenic SNPs
  revealed a common haplotype spanning 2.5 kb around the mutated
  nucleotide in the parents of both patients, suggesting ancestral origin
  of the mutation. The female patient had no breast development despite
  normal menstruation, a phenotype different from that seen in women with
  the R527H mutation (150330.0021).
  
  .0038
  MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
  LMNA, GLN493TER 
  
  In a German woman with LGMD1B (159001), Rudnik-Schoneborn et al. (2007)
  identified a heterozygous 1477C-T transition in exon 8 of the LMNA gene,
  resulting in a gln493-to-ter (Q493X) substitution. She presented with
  slowly progressive proximal muscle weakness beginning in the lower
  extremities and later involving the upper extremities. EMG showed both
  neurogenic and myopathic defects in the quadriceps muscle. At age 53
  years, she was diagnosed with atrioventricular conduction block and
  arrhythmia requiring pacemaker implantation. Family history showed that
  her mother had walking difficulties from age 40 years and died of a
  heart attack at age 54. Six other deceased family members had suspected
  cardiomyopathy without muscle involvement.
  
  .0039
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  LMNA, IVS8, G-C, +5 
  
  Morel et al. (2006) reported 2 sisters, the children of
  nonconsanguineous Punjabi parents, with familial partial lipodystrophy
  type 2 (FPLD2; 151660). The first presented with acanthosis nigricans at
  age 5 years, diabetes with insulin resistance, hypertension, and
  hypertriglyceridemia at age 13 years, and partial lipodystrophy starting
  at puberty. Her sister and their mother had a similar metabolic profile
  and physical features, and their mother died of vascular disease at age
  32 years. LMNA sequencing showed that the sisters were each heterozygous
  for a novel G-to-C mutation at the intron 8 consensus splice donor site,
  which was absent from the genomes of 300 healthy individuals. The
  retention of intron 8 in mRNA predicted a prematurely truncated lamin A
  isoform (516 instead of 664 amino acids) with 20 nonsense 3-prime
  terminal residues. The authors concluded that this was the first LMNA
  splicing mutation to be associated with FPLD2, and that it causes a
  severe clinical and metabolic phenotype.
  
  .0040
  HUTCHINSON-GILFORD PROGERIA SYNDROME
  LMNA, VAL607VAL 
  
  In a patient with a severe form of HGPS (176670), Moulson et al. (2007)
  identified a de novo heterozygous 1821G-A transition in exon 11 of the
  LMNA gene, resulting in a val607-to-val (V607V) substitution. The
  1821G-A mutation favored the use of the same cryptic splice site as the
  common 1824C-T mutation (150330.0022) and produced the same resultant
  progerin product. However, the ratio of mutant to wildtype mRNA and
  protein was increased in the patient compared to typical HGPS cells. The
  patient had flexion contractures, thick and tight skin, and other severe
  progeroid features. He died of infection at 26 days of age.
  
  .0041
  CARDIOMYOPATHY, DILATED, 1A
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL, INCLUDED;;
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2, INCLUDED
  LMNA, SER573LEU 
  
  In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with
  conduction defects (CMD1A; 115200), Taylor et al. (2003) identified
  heterozygosity for a 1718C-T transition in exon 11 of the LMNA gene,
  resulting in a ser573-to-leu substitution at a highly conserved residue,
  predicted to affect the carboxyl tail of the lamin A isoform. The
  mutation was not found in the proband's 2 unaffected offspring or in 300
  control chromosomes, but her unaffected 60-year-old sister also carried
  the mutation.
  
  Van Esch et al. (2006) analyzed the LMNA gene in a 44-year-old male of
  European descent with arthropathy, tendinous calcifications, and a
  progeroid appearance (see 248370) and identified homozygosity for the
  S573L mutation. Progeroid features included a small pinched nose, small
  lips, micrognathia with crowded teeth, cataract, and alopecia. He also
  had generalized lipodystrophy, and sclerodermatous skin. The arthropathy
  affected predominantly the distal femora and proximal tibia in the knee
  with tendinous calcifications. However, he had normal clavicles and no
  evidence of acroosteolysis. The authors concluded that he had a novel
  phenotype. The patient's unaffected 15-year-old son was heterozygous for
  the mutation, which was not found in 450 control chromosomes. The
  authors noted that the patient had no evidence of cardiomyopathy and his
  70-year-old mother, an obligate heterozygote, had no known cardiac
  problems.
  
  In a 75-year-old European male with partial lipodystrophy (151660),
  Lanktree et al. (2007) identified heterozygosity for the S573L mutation
  in the LMNA gene.
  
  .0042
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  LMNA, ASP230ASN 
  
  In a 46-year-old South Asian female with partial lipodystrophy (151660),
  Lanktree et al. (2007) identified heterozygosity for a 688G-A transition
  in exon 4 of the LMNA gene, resulting in an asp230-to-asn (D230N)
  substitution at a conserved residue located 5-prime to the nuclear
  localization signal. The mutation, predicted to affect only the lamin A
  isoform, was not found in 200 controls of multiple ethnic backgrounds.
  
  .0043
  LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
  LMNA, ARG399CYS 
  
  In a 50-year-old European female with partial lipodystrophy (151660),
  Lanktree et al. (2007) identified heterozygosity for a 1195C-T
  transition in exon 7 of the LMNA gene, resulting in an arg399-to-cys
  (R399C) substitution at a conserved residue located 5-prime to the
  nuclear localization signal. The mutation, predicted to affect only the
  lamin A isoform, was not found in 200 controls of multiple ethnic
  backgrounds.
  
  Decaudain et al. (2007) identified a heterozygous R399 mutation in a
  woman with severe metabolic syndrome. She was diagnosed with
  insulin-resistant diabetes at age 32. Chronic hyperglycemia led to
  retinopathy, peripheral neuropathy, and renal failure. She had severe
  hypertriglyceridemia and diffuse atherosclerosis, requiring coronary
  artery bypass at age 49. Physical examination revealed android fat
  distribution with lipoatrophy of lower limbs and calves hypertrophy
  without any muscle weakness. Her mother and a brother had diabetes and
  died several years earlier.
  
  .0044
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL
  LMNA, VAL440MET
  
  In a 27-year-old Italian woman with a mandibuloacral dysplasia type A
  (MADA; 248370)-like phenotype, Lombardi et al. (2007) found compound
  heterozygosity for missense mutations in the LMNA cDNA: a G-to-A
  transition at position 1318 in exon 7 that gave rise to a val-to-met
  substitution at codon 440 (V440M), and an R527H substitution
  (150330.0021). Each healthy parent was a simple heterozygote for one or
  the other mutation. The apparent MADA phenotype was associated with
  muscular hyposthenia and generalized hypotonia. Clavicular hypoplasia
  and metabolic imbalances were absent. Lombardi et al. (2007)
  hypothesized that lack of homozygosity for the R527H mutation attenuated
  the MADA phenotype, while the V440M mutation may have contributed to
  both the muscle phenotype and the pathogenic effect of the single R527H
  mutation.
  
  .0045
  HEART-HAND SYNDROME, SLOVENIAN TYPE
  LMNA, IVS9AS, T-G, -12
  
  In affected members of a Slovenian family with heart-hand syndrome
  (610140), originally reported by Sinkovec et al. (2005), Renou et al.
  (2008) identified heterozygosity for a T-G transversion in intron 9 of
  the LMNA gene (IVS9-12T-G), predicted to cause a frameshift and
  premature truncation in exon 10, with the addition of 14 new amino acids
  at the C terminus. The mutation was not found in unaffected family
  members or in 100 healthy controls. Analysis of fibroblasts from 2
  affected individuals confirmed the presence of truncated protein and
  revealed aberrant localization of lamin A/C accumulated in intranuclear
  foci as well as dysmorphic nuclei with nuclear envelope herniations.
  
  .0046
  MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
  LMNA, ALA529THR 
  
  In a 56-year-old Japanese woman, born of consanguineous parents, with
  mandibuloacral dysplasia and type A lipodystrophy (248370), Kosho et al.
  (2007) identified a homozygous 1585G-A transition in exon 9 of the LMNA
  gene, resulting in an ala529-to-thr (A529T) substitution. The authors
  stated that she was the oldest reported patient with the disorder. In
  addition to classic MAD with lipodystrophy type A phenotype, including
  progeroid appearance, acroosteolysis of the distal phalanges, and loss
  of subcutaneous fat in the limbs, she had severe progressive destructive
  skeletal and osteoporotic changes. Vertebral collapse led to paralysis.
  However, Kosho et al. (2007) also noted that other factors may have
  contributed to the severe osteoporosis observed in this patient. Another
  mutation in this codon, A529V (150330.0037), results in a similar
  phenotype.
  
  .0047
  MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
  LMNA, LEU380SER
  
  In a 7-year-old boy with a LNMA-related congenital muscular dystrophy
  (613205), Quijano-Roy et al. (2008) identified a de novo heterozygous
  mutation in exon 6 of the LMNA gene, resulting in a leu380-to-ser
  (L380S) substitution. He showed decreased movements in utero, hypotonia,
  talipes foot deformities, no head or trunk control, distal joint
  contractures, respiratory insufficiency, and paroxysmal atrial
  tachycardia. Serum creatine kinase was increased, and muscle biopsy
  showed dystrophic changes.
  
  .0048
  MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
  LMNA, ARG249TRP 
  
  In a 9-year-old girl with congenital muscular dystrophy (613205),
  Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in
  exon 4 of the LMNA gene, resulting in an arg249-to-trp (R249W)
  substitution. She presented at age 3 to 6 months with axial weakness and
  talipes foot deformities. She lost head support at 9 months, had
  respiratory insufficiency, joint contractures, and axial and limb muscle
  weakness. A de novo heterozygous R249W mutation was also identified in
  an unrelated 3-year-old boy with congenital LGMD1B who showed decreased
  movements in utero, hypotonia, distal contractures, no head or trunk
  control, and respiratory insufficiency. Both patients had increased
  serum creatine kinase and showed myopathic changes on EMG studies.
  
  .0049
  EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
  MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED, INCLUDED;;
  MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B, INCLUDED
  LMNA, GLU358LYS 
  
  Mercuri et al. (2004) identified a de novo heterozygous 1072G-A
  transition in exon 5 of the LMNA gene, resulting in a glu358-to-lys
  (E358K) substitution in 5 unrelated patients with muscular dystrophy.
  Three patients had the common phenotype of autosomal dominant
  Emery-Dreifuss muscular dystrophy (181350), 1 had early-onset LGMD1B
  (159001), and the last had had a more severe disorder consistent with
  congenital muscular dystrophy (613205). The mutation was not identified
  in 150 controls. The patient with LGMD1B also had cardiac conduction
  abnormalities, respiratory failure, and features of lipodystrophy
  (151660). Mercuri et al. (2004) commented on the extreme phenotypic
  variability associated with this mutation.
  
  In 4 unrelated patients with LMNA-related congenital muscular dystrophy,
  Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in
  exon 6 of the LMNA gene, resulting in a glu358-to-lys (E358K)
  substitution. Three patients presented before 1 year of age with
  hypotonia and later developed head drop with neck muscle weakness. There
  was delayed motor development with early loss of ambulation, distal limb
  contractures, axial and limb muscle weakness, respiratory insufficiency
  requiring mechanical ventilation, increased serum creatine kinase, and
  dystrophic changes on muscle biopsy. One patient developed ventricular
  tachycardia at age 20 years. The fourth patient with congenital LGMD1B
  had decreased fetal movements and presented at age 3 to 6 months with
  hypotonia, loss of head control, and delayed motor development.
  
  .0050
  MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
  LMNA, 3-BP DEL, 94AAG
  
  In an 18-month-old boy with LMNA-related congenital muscular dystrophy
  (613205), D'Amico et al. (2005) identified a de novo heterozygous 3-bp
  deletion (94delAAG) in exon 1 of the LMNA gene, resulting in the
  deletion of lys32. Although he had normal early motor development, he
  showed prominent neck extensor weakness resulting in a 'dropped head'
  phenotype at age 1 year. He was able to stand independently but had some
  difficulty walking.
  
  .0051
  VARIANT OF UNKNOWN SIGNIFICANCE
  LMNA, ARG644CYS
  
  An arg644-to-cys (R644C) mutation in the LMNA gene has been linked with
  several different phenotypic presentations (Genschel et al., 2001;
  Mercuri et al., 2005; Rankin et al., 2008); however, the pathogenicity
  of the mutation has not been confirmed (Moller et al., 2009).
  
  In a German patient with dilated cardiomyopathy with no history history
  of conduction system disease (see 152000), Genschel et al. (2001)
  identified heterozygosity for a 1930C-T transition in exon 11 of the
  LMNA gene resulting in an R644C substitution in the C-terminal domain of
  lamin A. The authors noted that the mutation is solely within lamin A,
  but not lamin C, whereas previously reported mutations causing dilated
  cardiomyopathy are located more in the rod domain of the protein.
  
  Mercuri et al. (2005) identified heterozygosity for the R644C mutation
  in 4 patients with skeletal and cardiac muscle involvement of varying
  severity. In 1 patient, the mutation was found in the affected brother
  and the unaffected father, and was not found in the affected mother. The
  mutation was not found in 100 unrelated control subjects.
  
  Rankin et al. (2008) described 9 patients in 8 families with the same
  mutation. Patients 1 and 2 presented with lipodystrophy and insulin
  resistance; patient 1 also had focal segmental glomerulosclerosis.
  Patient 3 presented with motor neuropathy, patient 4 with arthrogryposis
  and dilated cardiomyopathy with left ventricular noncompaction, patient
  5 with severe scoliosis and contractures, patient 6 with limb-girdle
  weakness, and patient 7 with hepatic steatosis and insulin resistance.
  Patients 8 and 9 were brothers who had proximal weakness and
  contractures. The same LMNA was identified in 9 unaffected individuals
  in these 9 families, but was not detected in 200 German and 300 British
  controls. Rankin et al. (2008) suggested that extreme phenotypic
  diversity and low penetrance are associated with the R644C mutation.
  
  .0052
  CARDIOMYOPATHY, DILATED, WITH HYPERGONADOTRIPIC HYPOGONADISM
  LMNA, LEU59ARG
  
  In a 17-year-old Caucasian female with dilated cardiomyopathy and
  ovarian failure (212112), Nguyen et al. (2007) identified heterozygosity
  for a de novo 176T-C transition in exon 1 of the LMNA gene, predicted to
  result in a leu59-to-arg (L59R) substitution. Analysis of nuclear
  morphology in patient fibroblasts showed more irregularity and variation
  than that of control fibroblasts, with denting, blebbing, and irregular
  margins. The mutation was not found in the unaffected parents or in 116
  population-based controls.
  
  In a 15-year-old Caucasian girl with dilated cardiomyopathy and ovarian
  failure who died from an arrhythmia while awaiting cardiac
  transplantation, McPherson et al. (2009) identified heterozygosity for
  the L59R mutation in the LMNA gene. The mutation was presumed to be de
  novo, although the unaffected parents declined DNA testing. The patient
  also had a healthy older sister, and there was no family history of
  cardiomyopathy or hypogonadism.
  
See Also:
  Krohne and Benavente (1986); Lebel and Raymond (1987)
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  show muscular and cardiac abnormalities. J. Clin. Endocr. Metab. 89:
  5337-5346, 2004.
  
  104. Varga, R.; Eriksson, M.; Erdos, M. R.; Olive, M.; Harten, I.;
  Kolodgie, F.; Capell, B. C.; Cheng, J.; Faddah, D.; Perkins, S.; Avallone,
  H.; San, H.; Qu, X.; Ganesh, S.; Gordon, L. B.; Virmani, R.; Wight,
  T. N.; Nabel, E. G.; Collins, F. S.: Progressive vascular smooth
  muscle cell defects in a mouse model of Hutchinson-Gilford progeria
  syndrome. Proc. Nat. Acad. Sci. 103: 3250-3255, 2006.
  
  105. Vigouroux, C.; Auclair, M.; Dubosclard, E.; Pouchelet, M.; Capeau,
  J.; Courvalin, J.-C.; Buendia, B.: Nuclear envelope disorganization
  in fibroblasts from lipodystrophic patients with heterozygous R482Q/W
  mutations in the lamin A/C gene. J. Cell Sci. 114: 4459-4468, 2001.
  
  106. Vigouroux, C.; Caux, F. Capeau, J.; Christin-Maitre, S.; Cohen,
  A.: LMNA mutations in atypical Werner's syndrome. (Letter) Lancet 362:
  1585 only, 2003.
  
  107. Weber, K.; Plessmann, U.; Traub, P.: Maturation of nuclear lamin
  A involves a specific carboxy-terminal trimming, which removes the
  polyisoprenylation site from the precursor; implications for the structure
  of the nuclear lamina. FEBS Lett. 257: 411-414, 1989.
  
  108. Worman, H. J.; Bonne, G.: 'Laminopathies': a wide spectrum of
  human diseases. Exp. Cell Res. 313: 2121-2133, 2007.
  
  109. Wuyts, W.; Biervliet, M.; Reyniers, E.; D'Apice, M. R.; Novelli,
  G.; Storm, K.: Somatic and gonadal mosaicism in Hutchinson-Gilford
  progeria. Am. J. Med. Genet. 135A: 66-68, 2005.
  
  110. Wydner, K. L.; McNeil, J. A.; Lin, F.; Worman, H. J.; Lawrence,
  J. B.: Chromosomal assignment of human nuclear envelope protein genes
  LMNA, LMNB1, and LBR by fluorescence in situ hybridization. Genomics 32:
  474-478, 1996.
  
  111. Yang, S. H.; Andres, D. A.; Spielmann, H. P.; Young, S. G.; Fong,
  L. G.: Progerin elicits disease phenotypes of progeria in mice whether
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  112. Yang, S. H.; Bergo, M. O.; Toth, J. I.; Qiao, X.; Hu, Y.; Sandoval,
  S.; Meta, M.; Bendale, P.; Gelb, M. H.; Young, S. G.; Fong, L. G.
  : Blocking protein farnesyltransferase improves nuclear blebbing in
  mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome
  mutation. Proc. Nat. Acad. Sci. 102: 10291-10296, 2005.
  
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  inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford
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  LMNA mutation R471C with new phenotype: mandibuloacral dysplasia,
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Contributors: 
  Marla J. F. O'Neill - updated: 10/19/2010
  Cassandra L. Kniffin - updated: 10/13/2010
  Paul J. Converse - updated: 9/20/2010
  Patricia A. Hartz - updated: 8/10/2010
  Patricia A. Hartz - updated: 7/27/2010
  Cassandra L. Kniffin - updated: 4/7/2010
  Nara Sobreira - updated: 1/8/2010
  Cassandra L. Kniffin - updated: 1/5/2010
  Cassandra L. Kniffin - updated: 11/2/2009
  George E. Tiller - updated: 8/3/2009
  Cassandra L. Kniffin - updated: 7/9/2009
  Patricia A. Hartz - updated: 6/30/2009
  George E. Tiller - updated: 5/13/2009
  George E. Tiller - updated: 4/22/2009
  George E. Tiller - updated: 4/16/2009
  Cassandra L. Kniffin - updated: 3/5/2009
  Marla J. F. O'Neill - updated: 2/19/2009
  George E. Tiller - updated: 11/19/2008
  Paul J. Converse - updated: 10/27/2008
  John A. Phillips, III - updated: 9/23/2008
  George E. Tiller - updated: 6/5/2008
  Cassandra L. Kniffin - updated: 1/30/2008
  Marla J. F. O'Neill - updated: 11/21/2007
  Cassandra L. Kniffin - updated: 11/7/2007
  George E. Tiller - updated: 10/31/2007
  Cassandra L. Kniffin - updated: 10/16/2007
  John A. Phillips, III - updated: 7/17/2007
  George E. Tiller - updated: 6/13/2007
  Cassandra L. Kniffin - updated: 5/2/2007
  John A. Phillips, III - updated: 4/9/2007
  John A. Phillips, III - updated: 3/22/2007
  Marla J. F. O'Neill - updated: 3/8/2007
  Ada Hamosh - updated: 8/1/2006
  Cassandra L. Kniffin - updated: 6/26/2006
  Patricia A. Hartz - updated: 3/28/2006
  Marla J. F. O'Neill - updated: 3/22/2006
  Marla J. F. O'Neill - updated: 2/15/2006
  Victor A. McKusick - updated: 2/1/2006
  Marla J. F. O'Neill - updated: 7/5/2005
  Marla J. F. O'Neill - updated: 6/1/2005
  George E. Tiller - updated: 5/19/2005
  Victor A. McKusick - updated: 5/11/2005
  John A. Phillips, III - updated: 4/13/2005
  Victor A. McKusick - updated: 3/15/2005
  Victor A. McKusick - updated: 2/22/2005
  Victor A. McKusick - updated: 2/17/2005
  Marla J. F. O'Neill - updated: 11/3/2004
  Patricia A. Hartz - updated: 10/27/2004
  Victor A. McKusick - updated: 10/12/2004
  Cassandra L. Kniffin - reorganized: 5/3/2004
  Cassandra L. Kniffin - updated: 4/15/2004
  Victor A. McKusick - updated: 2/25/2004
  Patricia A. Hartz - updated: 2/17/2004
  Victor A. McKusick - updated: 2/9/2004
  Victor A. McKusick - updated: 1/20/2004
  Cassandra L. Kniffin - updated: 1/6/2004
  Victor A. McKusick - updated: 10/22/2003
  Victor A. McKusick - updated: 10/1/2003
  John A. Phillips, III - updated: 8/25/2003
  Victor A. McKusick - updated: 6/11/2003
  Ada Hamosh - updated: 5/28/2003
  Ada Hamosh - updated: 4/29/2003
  Ada Hamosh - updated: 4/23/2003
  Ada Hamosh - updated: 4/16/2003
  Cassandra L. Kniffin - updated: 12/16/2002
  George E. Tiller - updated: 10/28/2002
  Victor A. McKusick - updated: 8/16/2002
  Victor A. McKusick - updated: 3/21/2002
  John A. Phillips, III - updated: 11/6/2001
  John A. Phillips, III - updated: 10/4/2001
  John A. Phillips, III - updated: 7/16/2001
  John A. Phillips, III - updated: 3/16/2001
  Victor A. McKusick - updated: 1/2/2001
  George E. Tiller - updated: 8/16/2000
  Victor A. McKusick - updated: 7/20/2000
  Victor A. McKusick - updated: 4/13/2000
  Paul Brennan - updated: 4/10/2000
  Victor A. McKusick - updated: 1/28/2000
  Victor A. McKusick - updated: 12/14/1999
  Victor A. McKusick - updated: 12/3/1999
  Victor A. McKusick - updated: 2/23/1999
  Alan F. Scott - updated: 4/22/1996
  
Creation Date: 
  Victor A. McKusick: 1/5/1988
  
Edit Dates: 
  carol: 12/07/2010
  carol: 10/19/2010
  wwang: 10/19/2010
  ckniffin: 10/13/2010
  mgross: 9/20/2010
  mgross: 8/16/2010
  terry: 8/10/2010
  mgross: 8/6/2010
  terry: 7/27/2010
  wwang: 4/13/2010
  ckniffin: 4/7/2010
  ckniffin: 2/24/2010
  carol: 1/15/2010
  ckniffin: 1/11/2010
  carol: 1/8/2010
  carol: 1/6/2010
  ckniffin: 1/5/2010
  wwang: 11/5/2009
  ckniffin: 11/2/2009
  wwang: 8/3/2009
  ckniffin: 7/9/2009
  alopez: 7/7/2009
  terry: 6/30/2009
  wwang: 6/25/2009
  terry: 6/3/2009
  terry: 5/13/2009
  wwang: 5/7/2009
  terry: 4/22/2009
  alopez: 4/16/2009
  wwang: 3/11/2009
  ckniffin: 3/5/2009
  carol: 2/24/2009
  wwang: 2/23/2009
  terry: 2/19/2009
  wwang: 11/19/2008
  mgross: 10/27/2008
  alopez: 9/23/2008
  wwang: 6/11/2008
  terry: 6/5/2008
  wwang: 2/1/2008
  ckniffin: 1/30/2008
  carol: 11/26/2007
  terry: 11/21/2007
  wwang: 11/20/2007
  ckniffin: 11/7/2007
  alopez: 11/6/2007
  terry: 10/31/2007
  wwang: 10/25/2007
  ckniffin: 10/16/2007
  terry: 9/20/2007
  alopez: 7/17/2007
  wwang: 6/14/2007
  terry: 6/13/2007
  wwang: 6/8/2007
  wwang: 5/11/2007
  ckniffin: 5/2/2007
  carol: 4/9/2007
  alopez: 3/22/2007
  wwang: 3/12/2007
  terry: 3/8/2007
  wwang: 8/9/2006
  alopez: 8/3/2006
  terry: 8/1/2006
  wwang: 7/5/2006
  ckniffin: 6/26/2006
  wwang: 3/29/2006
  terry: 3/28/2006
  wwang: 3/22/2006
  wwang: 2/23/2006
  terry: 2/15/2006
  alopez: 2/15/2006
  terry: 2/3/2006
  terry: 2/1/2006
  terry: 10/12/2005
  wwang: 7/8/2005
  terry: 7/5/2005
  alopez: 6/13/2005
  wwang: 6/8/2005
  wwang: 6/1/2005
  tkritzer: 5/25/2005
  terry: 5/19/2005
  wwang: 5/18/2005
  wwang: 5/11/2005
  wwang: 4/13/2005
  wwang: 3/22/2005
  wwang: 3/18/2005
  terry: 3/16/2005
  terry: 3/15/2005
  carol: 3/8/2005
  wwang: 3/7/2005
  terry: 2/22/2005
  terry: 2/21/2005
  terry: 2/17/2005
  joanna: 2/9/2005
  carol: 12/8/2004
  tkritzer: 12/7/2004
  tkritzer: 11/4/2004
  terry: 11/3/2004
  mgross: 10/27/2004
  tkritzer: 10/15/2004
  terry: 10/12/2004
  terry: 6/28/2004
  tkritzer: 5/10/2004
  carol: 5/4/2004
  carol: 5/3/2004
  ckniffin: 4/29/2004
  ckniffin: 4/28/2004
  ckniffin: 4/27/2004
  ckniffin: 4/15/2004
  cwells: 3/4/2004
  tkritzer: 2/26/2004
  terry: 2/25/2004
  cwells: 2/23/2004
  terry: 2/17/2004
  cwells: 2/16/2004
  terry: 2/9/2004
  carol: 1/21/2004
  terry: 1/20/2004
  tkritzer: 1/13/2004
  ckniffin: 1/6/2004
  terry: 11/11/2003
  tkritzer: 10/24/2003
  alopez: 10/22/2003
  tkritzer: 10/22/2003
  tkritzer: 10/7/2003
  tkritzer: 10/1/2003
  alopez: 8/25/2003
  alopez: 7/7/2003
  tkritzer: 6/25/2003
  tkritzer: 6/24/2003
  terry: 6/11/2003
  alopez: 5/28/2003
  terry: 5/28/2003
  alopez: 5/9/2003
  alopez: 4/30/2003
  terry: 4/29/2003
  alopez: 4/25/2003
  alopez: 4/23/2003
  joanna: 4/23/2003
  alopez: 4/16/2003
  terry: 4/16/2003
  ckniffin: 4/10/2003
  tkritzer: 2/28/2003
  carol: 1/3/2003
  tkritzer: 12/23/2002
  ckniffin: 12/16/2002
  cwells: 11/19/2002
  terry: 11/15/2002
  cwells: 10/28/2002
  tkritzer: 8/23/2002
  tkritzer: 8/22/2002
  terry: 8/16/2002
  alopez: 4/19/2002
  carol: 4/2/2002
  alopez: 3/27/2002
  terry: 3/21/2002
  mcapotos: 12/21/2001
  alopez: 11/6/2001
  cwells: 10/8/2001
  cwells: 10/4/2001
  cwells: 7/20/2001
  cwells: 7/16/2001
  alopez: 3/16/2001
  cwells: 1/11/2001
  terry: 1/2/2001
  alopez: 8/16/2000
  mcapotos: 7/24/2000
  mcapotos: 7/20/2000
  mcapotos: 6/30/2000
  carol: 5/9/2000
  alopez: 5/8/2000
  terry: 4/13/2000
  alopez: 4/10/2000
  alopez: 2/1/2000
  terry: 1/28/2000
  alopez: 12/14/1999
  carol: 12/14/1999
  mgross: 12/3/1999
  terry: 12/3/1999
  alopez: 3/1/1999
  alopez: 2/26/1999
  terry: 2/23/1999
  terry: 4/22/1996
  mark: 4/22/1996
  mark: 12/7/1995
  carol: 10/1/1993
  carol: 8/14/1992
  supermim: 3/16/1992
  supermim: 3/20/1990
  supermim: 2/3/1990
  ddp: 10/27/1989
  
OMIM
DBGET integrated database retrieval system