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Database: OMIM
Entry: 300461
LinkDB: 300461
MIM Entry: 300461
Title:
  *300461 ORNITHINE CARBAMOYLTRANSFERASE; OTC
  ;;ORNITHINE TRANSCARBAMYLASE
Text:
  
  DESCRIPTION
  
  Ornithine carbamoyltransferase (EC 2.1.3.3) is a nuclear-encoded
  mitochondrial matrix enzyme that catalyzes the second step of the urea
  cycle in mammals.
  
  CLONING
  
  - Rat Gene
  
  Using rat liver OTC mRNA, Horwich et al. (1983) isolated and
  characterized a cDNA corresponding to the OTC gene. The translated
  polypeptide has a molecular mass of 40 kD, but the authors noted that
  the mature, active enzyme is a trimer of identical 36-kD subunits,
  indicating posttranslational modification.
  
  - Human Gene
  
  Horwich et al. (1984) determined that the human OTC gene encodes a
  354-amino acid protein which is synthesized on free cytoplasmic
  polyribosomes as a precursor of about 40 kD. This pre-OTC has an
  NH2-extension which is cleaved proteolytically concomitant with its
  posttranslational energy-dependent import into mitochondria. The OTC
  enzyme is synthesized in the cytoplasm and is directed to mitochondria
  by a 32-residue amino-terminal leader peptide. The protein sequence
  resembles that of both OTC and aspartate transcarbamylase from E. coli
  (see also Horwich et al., 1985).
  
  To define the critical residues and/or regions in the OTC leader
  peptide, Horwich et al. (1986) synthesized OTC precursors with
  alterations in the leader portion. Analysis of deletions revealed that
  the mid-portion of the 32-residue leader peptide is an absolute
  requirement for both mitochondrial uptake and proteolytic processing.
  Further analysis of precursors with single substitutions revealed
  complete loss of function when arginine 23 was substituted with glycine.
  The critical role of this arginine residue may be mediated by
  participation in a local secondary structure, very likely an
  alpha-helix. In a review of the subject, Hurt and van Loon (1986)
  presented evidence that the amino-terminal presequences also contain
  information for 'intramitochondrial sorting.'
  
  Tuchman et al. (1995) noted that the subunits of the human OTC
  homotrimer show 46% amino acid sequence homology to the catalytic
  subunit of E. coli aspartate transcarbamylase. Secondary structure
  predictions, distributions of hydrophilic and hydrophobic regions, and
  the pattern of conserved residues suggest that the 3-dimensional
  structures of the 2 proteins are likely to be similar.
  
  GENE STRUCTURE
  
  Hata et al. (1986, 1988) determined that the human OTC gene contains 10
  exons and spans approximately 73 kb.
  
  MAPPING
  
  By in situ hybridization using DNA complementary to the human OTC gene,
  Lindgren et al. (1984) mapped the gene to Xp21.1. Studies of the
  chromosomes of a female with Duchenne muscular hypertrophy and
  t(X;9)(p21;p22) indicated that OTC is proximal to DMD on Xp; the
  derivative chromosome 9 showed no hybridization with the OTC probe.
  
  MOLECULAR GENETICS
  
  Rozen et al. (1985) gave the first reported example of an OTC gene
  deletion that could be identified cytogenetically in a patient with OTC
  deficiency (311250).
  
  In a boy with a mild form of OTC deficiency, Maddalena et al. (1988)
  found somatic mosaicism for an intragenic deletion of the OTC gene
  (300461.0001). In 3 of 24 unrelated patients with OTC deficiency,
  Maddalena et al. (1988) identified 2 different point mutations in the
  same codon of the OTC gene (300461.0002-300461.0003). The patients
  included 2 males with severe neonatal onset and a female patient with
  mild disease. Using the method of chemical mismatch cleavage developed
  by Cotton et al. (1988), Grompe et al. (1989) identified 4 mutations and
  a polymorphism in the OTC gene (300461.0004-300461.0009) in 5 unrelated
  patients with OTC deficiency. Grompe et al. (1991) reported further on
  the use of chemical mismatch cleavage. Primers for specific
  amplification of OTC exons 1, 3, 5, 9, and 10 were also used to detect
  alterations in TaqI sites in exons 1, 3, 5, and 9. With a combination of
  molecular techniques, accurate diagnostic evaluation was possible in 17
  of 18 families.
  
  In a catalog of mutations in the OTC gene, Tuchman (1993) reported
  deletions of variable size involving one or more exons, 29 different
  missense, nonsense, or frameshift mutations, and 3 polymorphisms in
  patients with OTC deficiency. Approximately 10 to 15% of all molecular
  alterations associated with OTC deficiency were large deletions
  involving all or part of the OTC gene. Most of the remaining mutations
  were unique to the affected family. Two mutations had been found in the
  sequence of the 'leader' peptide, 23 in the coding sequence of the
  'mature' enzyme, and 4 in splicing recognition sites. Tuchman et al.
  (1995) tabulated 40 known mutations in the OTC gene resulting in enzyme
  deficiency, and described the predicted effects of all known mutations
  and deletions on the structure and function of the mature enzyme.
  Mutations in the OTC gene found in patients with hyperammonemia of the
  'neonatal type' were clustered in important structural or functional
  domains, either in the interior of the protein, at the active site, or
  at the interchain interface, while mutations found in patients with
  milder 'late onset' disease were located primarily on the surface of the
  protein. Tuchman et al. (1996) estimated that approximately 90 different
  mutations associated with OTC deficiency had been defined. Large
  deletions of 1 or more exons were found in 8% of 78 affected families,
  small deletions or insertions of 1 to 5 bases were found in
  approximately 10% of affected families, and splice site mutations were
  found in 18% of families. Contrary to previous reports, recurrent point
  mutations seemed to be equally distributed among most CpG dinucleotides
  rather than showing prevalent mutations. No single point mutation had a
  relative frequency of more than 6.4%. Of the 64 families with nucleotide
  substitutions, 24 (38%) were G to A with the next most common being C to
  T (16%) and A to T (11%).
  
  Gilbert-Dussardier et al. (1996) described the first example of partial
  duplication of the OTC gene and 4 novel point mutations of this gene in
  patients with congenital hyperammonemia. Oppliger Leibundgut et al.
  (1996) identified 3 new and 3 known mutations in male patients with OTC
  deficiency and studied the frequency of 4 polymorphisms of the OTC gene.
  
  In 48 patients with OTC deficiency, Genet et al. (2000) identified
  mutations in the OTC gene. Fourteen of the mutations were previously
  unreported. Of the 48 identified mutations, 8 were large deletions, 8
  were nonsense mutations, 26 were missense mutations, 4 were splice site
  mutations, and 2 were small deletions.
  
  Tuchman et al. (2002) provided a comprehensive compilation of 244
  mutations, including 13 polymorphisms in the OTC gene; 24 of the
  mutations were reported for the first time. Acute neonatal
  hyperammonemia was the presenting phenotype in 42% of the
  disease-causing mutations; 21% were found in patients with late-onset
  disease and approximately 37% were found in manifesting heterozygous
  females, most of which were presumed to confer a neonatal phenotype in
  hemizygous males. The authors found that most mutations in the OTC gene
  are 'private' and are distributed throughout the gene with paucity of
  mutation in the sequence encoding the leader peptide (exon 1 and
  beginning of exon 2) and in exon 7. Almost all mutations in consensus
  splicing sites conferred a neonatal phenotype. Several of the 13
  polymorphisms are useful for allele tracking in patients in whom the
  mutation cannot be found. Even with sequencing of the entire reading
  frame and exon/intron boundaries, only about 80% of the mutations are
  detected in patients with proven OTC deficiency. The remaining probably
  occur within the introns or in regulatory domains.
  
  Yamaguchi et al. (2006) gave an update on the mutations found in the OTC
  gene: 341 mutations, of which 93 had not been previously reported, and
  an additional 29 nondisease-causing mutations and polymorphisms. Of the
  341 mutations, 149 were associated with neonatal onset of hyperammonemia
  (within the first week of life), 70 were seen in male patients with
  later onset of hyperammonemia, and 121 were found in heterozygous
  females. Most mutations in the OTC gene were specific to a particular
  family ('private' mutations). They were distributed throughout the gene,
  with a significant paucity of mutations in the 32 first codons encoding
  the 'leader' peptide (exon 1 and the beginning of exon 2). Almost all
  mutations in consensus splice sites conferred a neonatal-onset
  phenotype. Molecular screening methods identified mutations in about 80%
  of patients. Yamaguchi et al. (2006) suggested that the remaining
  patients may have mutations in regulatory domains or mutations deep in
  the introns, which constitute 98.5% of the genomic sequence. In
  addition, a phenocopy of OTC deficiency caused by mutations in another
  unknown gene could not be excluded.
  
  - Origin of Mutations
  
  Tuchman et al. (1995) used specific mutation analysis to estimate the
  proportion of males and females with OTC deficiency whose mutations
  occurred in the germ cells of one of the parents. The mutations were
  identified in the probands, and subsequently carrier testing was
  performed on their mothers and some of the grandmothers. Of 28
  OTC-deficient males, only 2 (7%) had sporadic mutations, whereas of 15
  OTC-deficient females, 12 (80%) had sporadic mutations. Based on these
  results, Tuchman et al. (1995) estimated that the mutation rate in male
  germ cells is about 50-fold higher than in female germ cells. Assuming a
  fitness for males with OTC deficiency of 0.0 and the proportion of new
  female mutants as 0.80, the estimated fitness of heterozygous females is
  0.4. Because of the difference in mutation rates between male and female
  germ cells, they suggested that nine-tenths or higher, rather than the
  conventional two-thirds proportion, be applied when estimating prior
  risk of carrier status in a mother of 1 affected male. The prior risk of
  a mother of an affected female is much lower, approximately two-tenths.
  
  Studying 13 unrelated girls with manifest OTC deficiency and their
  mothers, as well as 1 symptomatic and 3 asymptomatic adult females with
  proven carrier status, Oppliger Leibundgut et al. (1997) identified 15
  distinct single-base mutations, including 10 novel mutations. Sequence
  analysis of the DNA from the mothers of the 13 symptomatic girls
  revealed that only 1 of them was a carrier, thus confirming the high
  proportion of de novo mutations in heterozygous females.
  
  In a study of families with OTC deficiency from the literature pooled
  with a French series, Bonaiti-Pellie et al. (1990) concluded that
  segregation analysis provided no evidence for sporadic affected males,
  suggesting that there are virtually no mutations in eggs. They estimated
  that 57% of heterozygous females have the OTC gene on the basis of new
  mutations. The upper limit of the confidence interval, 16%, can be taken
  as the maximum prior probability that an affected male occurs as the
  result of a new mutation in his mother's germ cells.
  
  - X Inactivation
  
  To understand the correlation between X-inactivation status and the
  clinical phenotype of carrier females (which can vary from asymptomatic
  to severe hyperammonemia), Yorifuji et al. (1998) analyzed the
  X-inactivation pattern of peripheral blood leukocytes in a family
  consisting of a clinically normal mother and 2 daughters with severe
  manifestation. In addition, they obtained tissue samples from various
  parts of the liver of one of the daughters and analyzed X-inactivation
  patterns and residual OTC activities. The X inactivation of peripheral
  blood leukocytes was nearly random in these carrier females and showed
  no correlation with the disease phenotype; however, the X inactivation
  of the liver was much more skewed and correlated well with the OTC
  activity of all samples. The degree of X inactivation varied
  considerably, even within the same liver.
  
  ANIMAL MODEL
  
  The trait 'sparse fur' (spf) in the mouse is due to OTC deficiency
  (DeMars et al., 1976). Veres et al. (1987) demonstrated that the mutant
  OTC gene in the spf mouse contains a C-A transversion that alters a
  histidine residue to an asparagine residue at amino acid 117. The single
  base substitution in the cDNA for OTC from the mutant mouse was
  identified by means of a combination of 2 'new' techniques for rapid
  mutation analysis: ribonuclease A (RNase A) cleavage and the polymerase
  chain reaction (PCR) method for amplification of specific nucleotide
  sequences. The application of RNase A cleavage to localize the mutation,
  followed by PCR amplification of the mutated site, greatly simplified
  the procedure of mutation analysis (see also Ohtake et al., 1986).
  Wareham et al. (1987) used the OTC mutation in animals with the sparse
  fur trait (spf/Y or spf/spf) as a marker to demonstrate that there is an
  age-related reactivation of X-linked genes. They used mice with an
  X-autosome translocation that gives consistent nonrandom inactivation of
  the normal X. The normal X in these mice also carried a defective form
  of the histochemically demonstrable OTC enzyme. Only a small proportion
  of enzyme-positive cells was found in young animals. This proportion
  increased significantly with age, indicating a decrease in the stability
  of the X-inactivation mechanism.
  
Allelic Variants:
  .0001
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, DEL
  
  Maddalena et al. (1988) found somatic mosaicism for an intragenic
  deletion of the OTC gene in a boy with mild OTC deficiency (311250) who
  had a history of only 1 hospitalization for hyperammonemia and no
  evidence of neurologic injury at 6 years of age. In a boy in whom mild
  OTC deficiency was first diagnosed at the age of 8 months, Legius et al.
  (1990) also found somatic mosaicism for a deletion in the OTC gene.
  
  .0002
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG109GLN
  
  In 3 unrelated patients with OTC deficiency (311250), Maddalena et al.
  (1988) identified point mutations in the same arginine codon, number
  109. Two unrelated males with neonatal onset of severe OTC deficiency
  had a G-A change, resulting in an arg109-to-gln (R109Q) substitution. In
  a third case, that of a symptomatic heterozygous female, a C-T
  transition converted residue 109 to a premature stop (R109X;
  300461.0003). These results were interpreted as supporting the
  conclusion that TaqI restriction sites, which contain an internal CG,
  are particularly susceptible to C-T transition mutations due to
  deamination of a methylated C in either the sense or the antisense
  strand (the change in the antisense strand in the 2 males was a C-T
  transition.)
  
  By assays in COS-1 cells containing the R109Q OTC mutation, Lee and
  Nussbaum (1989) showed that the specific activity of the mutant OTC was
  100-fold lower than that of the wildtype.
  
  Strautnieks et al. (1991) identified the R109Q mutation in a female
  presenting at the age of 21 months with symptoms of OTC deficiency. The
  patient was identified by screening DNA from 29 families with at least
  one member with OTC deficiency. In 1 of 13 males with OTC deficiency,
  Suess et al. (1992) identified the R109Q mutation. In addition, they
  found deletions in 3 of the 13 patients: one involving the entire gene,
  a second with deletion of exons 7 and 8, and a third with deletion of
  exon 9.
  
  .0003
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG109TER
  
  See Maddalena et al. (1988) and 300461.0002.
  
  In a female patient with mild OTC deficiency (311250), Hata et al.
  (1989) demonstrated a C-T change in exon 5 of the OTC gene, resulting in
  a stop codon at residue 109 (arg109-to-ter; R109X).
  
  .0004
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, LEU111PRO
  
  In a patient with OTC deficiency (311250), Grompe et al. (1989) found a
  T-C mutation, resulting in a leu111-to-pro (L111P) change.
  
  .0005
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, GLN216GLU
  
  In a patient with OTC deficiency (311250), Grompe et al. (1989) found a
  C-G mutation, resulting in a gln216-to-glu (Q216E) change.
  
  .0006
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, GLU154TER
  
  In a patient with OTC deficiency (311250), Grompe et al. (1989)
  identified a nonsense mutation, glu154-to-ter (E154X).
  
  .0007
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, LEU45PRO
  
  In a patient with OTC deficiency (311250), Grompe et al. (1989)
  concluded that the disorder was caused by a T-A change that converted
  leu45-to-pro (L45P). The patient also carried a lys46-to-arg
  polymorphism (K46R; 300461.0009).
  
  .0008
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG26GLN
  
  In a patient with OTC deficiency (311250), Grompe et al. (1989) found a
  G-A change, resulting in an arg26-to-gln (R26Q) change.
  
  .0009
  ORNITHINE TRANSCARBAMYLASE POLYMORPHISM
  OTC, LYS46ARG
  
  In a patient with OTC deficiency (311250) caused by mutation in codon 45
  (leu45-to-pro; 300461.0007), Grompe et al. (1989) identified a
  lys46-to-arg (K46R) polymorphism in the OTC gene (see also Hata et al.,
  1988).
  
  .0010
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG245TRP
  
  In a family with OTC deficiency (311250), Finkelstein et al. (1990)
  identified a C-T change in the OTC gene, resulting in an arg245-to-trp
  (R245W) substitution. The patients showed some residual enzyme activity.
  
  .0011
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, GT-GC, INTRON 7
  
  In a patient with severe OTC deficiency (311250), Carstens et al. (1991)
  found a deletion of exon 7 of the OTC gene. A mutation in the 5-prime
  splice donor sequence at the junction between exon 7 and intron 7
  changed the second base such that the GT dinucleotide became GC. The
  mutation resulted in skipping of the preceding exon (see also
  300461.0012).
  
  .0012
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, GTA-GTG, INTRON 7
  
  In a patient with severe OTC deficiency (311250), Carstens et al. (1991)
  identified a deletion of exon 7 of the OTC gene. A mutation in the
  5-prime splice donor sequence at the junction between exon 7 and intron
  7 changed the second base such that there was an A-G change in the third
  position of the intron. The mutation resulted in skipping of the
  preceding exon (see also 300461.0011).
  
  .0013
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, IVS4, A-T, -2
  
  In a case of severe OTC deficiency (311250), Carstens et al. (1991)
  found an A-T change in the 3-prime splice acceptor AG dinucleotide at
  the end of intron 4, making this region an unacceptable splice junction.
  As a result, a cryptic 3-prime splice acceptor within exon 5 was used,
  producing a deletion of the first 12 bp of exon 5 and the resulting
  mRNA.
  
  .0014
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG277TRP
  
  In 2 unrelated males with mild OTC deficiency (311250), Hata et al.
  (1991) identified a C-T change, resulting in an arg277-to-trp (R277W)
  substitution. In each family the affected male had an asymptomatic
  brother hemizygous for the mutation.
  
  .0015
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, PRO225LEU
  
  Hentzen et al. (1991) described a family in which a proband and his
  maternal uncle and maternal great-uncle died in the neonatal period with
  hyperammonemia caused by OTC deficiency (311250). The mother and
  maternal grandmother of the proband showed a dramatic increment of
  urinary orotic acid following protein load, confirming their status as
  carriers. Using PCR amplification of OTC-specific mRNA derived from a
  postmortem biopsy of the liver of the proband, Hentzen et al. (1991)
  found that the MspI site (CCGG) in exon 7 was abolished. They identified
  a C-T transition in the OTC gene, resulting in a pro225-to-leu (P225L)
  substitution.
  
  .0016
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, GLU87LYS
  
  In order to improve the efficiency of screening for mutant OTC genotypes
  in cases of OTC deficiency (311250), Feldmann et al. (1992) focused on
  the carbamyl phosphate-binding domain (encoded by the third exon) and
  the MspI restriction sites (CCGG) of the coding sequence (located in
  exons 2 and 7), as they contain mutation hotspots, i.e., CpG
  dinucleotides. Using this strategy, Feldmann et al. (1992) identified 3
  'new' mutant genotypes. One of the new mutations was a glu87-lys (E87K)
  mutation found in a male baby who did well for the first 3.5 months of
  life, but thereafter lost his appetite and failed to thrive. Vomiting,
  agitation, abnormal movements, and generalized seizures occurred at 7.5
  months of age, and he rapidly fell into a deep terminal coma with liver
  enlargement and hepatic failure.
  
  .0017
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, GLY50TER
  
  Feldmann et al. (1992) found a gly50-to-ter (G50X) nonsense mutation in
  the OTC gene in a girl who was first admitted to hospital at the age of
  8 months because of poor weight gain and vomiting. Hereditary fructose
  intolerance was first considered because of liver failure, but
  persistent hyperammonemia and increased urinary orotic acid led to the
  diagnosis of OTC deficiency (311250). Despite a low protein diet and
  arginine administration, the patient had repeated attacks of
  hyperammonemia. An orthotopic liver transplant was carried out at 5
  years of age. Three years later the child was doing well on
  immunosuppressive agents.
  
  .0018
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, GLY162ARG
  
  In a male who died in deep coma at the age of 2 days, Feldmann et al.
  (1992) identified a glu162-to-arg (E162R) mutation, confirming OTC
  deficiency (311250).
  
  .0019
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, 1-BP DEL, 403G
  
  In a male with neonatal onset of hyperammonemia due to OTC deficiency
  (311250), Tuchman et al. (1992) identified a 1-bp deletion in exon 5 of
  the OTC gene, a loss of guanine-403, causing a frameshift.
  
  .0020
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, IVS2, G-A, -1
  
  In a male with neonatal onset of hyperammonemia caused by OTC deficiency
  (311250), Tuchman et al. (1992) identified a G-A transition in the OTC
  gene at the 3-prime end of intron 2 involving nucleotide 217 (-1),
  resulting in an acceptor splicing site error.
  
  .0021
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, GLY47GLU
  
  In a male with neonatal onset of hyperammonemia caused by OTC deficiency
  (311250), Tuchman et al. (1992) identified a 236G-A transition in the
  OTC gene, resulting in a gly47-to-glu (G47E) substitution.
  
  .0022
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG62THR
  
  In a male in whom onset of clinical problems associated with OTC
  deficiency (311250) occurred after the neonatal period, Tuchman et al.
  (1992) identified a 281G-C transversion in exon 3 of the OTC gene,
  resulting in an arg62-to-thr (R62T) substitution. This substitution
  changed the composition of the putative active site for carbamyl
  phosphate.
  
  .0023
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, LEU272PHE
  
  In a male in whom onset of clinical problems associated with OTC
  deficiency (311250) occurred after the neonatal period, Tuchman et al.
  (1992) found a 912G-T transversion in exon 9 of the OTC gene, resulting
  in a leu272-to-phe (L272F) substitution. This changed a conserved domain
  of the gene, likely to be the ornithine binding site.
  
  .0024
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, TYR313ASP
  
  In a female with OTC deficiency (311250), Tuchman et al. (1992) found a
  1033T-G transversion in the OTC gene, resulting in a tyr313-to-asp
  (Y313D) substitution.
  
  .0025
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG129HIS
  
  In affected patients from 2 Spanish families with OTC deficiency
  (311250), Garcia-Perez et al. (1995) identified an arg129-to-his (R129H)
  mutation in exon 4 of the OTC gene. The mutation results in the loss of
  a unique MspI restriction site that can be used for rapid diagnosis. The
  same mutation is found in the small spf-ash mouse, a rodent model of
  mild OTC deficiency, causing a neutral R129H mutation and inefficient
  splicing at the 5-prime donor site at the exon 4/intron 4 junction, with
  resultant 4 to 7% residual OTC activity. The mutation was found in the
  mother in one case, and arose de novo in the second case. Residual OTC
  activity, determined in a male and a female patient, was 1.3 and 3.5% of
  normal, respectively. Despite this low activity, the surviving patients
  had developed normally. One of them had reached reproductive age,
  raising the possibility of paternal transmission of the defect.
  
  .0026
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, LEU148PHE
  
  Komaki et al. (1997) identified a leu148-to-phe (L148F) substitution of
  the OTC gene in a 2-year-old girl with OTC deficiency (311250). OTC
  enzyme activity was 14% of control. Two elder sisters had died in
  childhood of hyperammonemia from OTC deficiency, and the patient also
  died of OTC deficiency. Enzyme activity in COS-1 cells transfected with
  the mutant cDNA was undetectable. Gene analysis showed that the mother
  had wildtype OTC alleles on both X chromosomes, and that the father was
  a mosaic for the mutant allele in his lymphocytes and spermatozoa. Thus,
  somatic and germline mosaicism led to the unusual pattern of X-linked
  inheritance in this family. Komaki et al. (1997) speculated about the
  possibility that skewed X inactivation, possibly due to inherited
  factors, was involved in this family.
  
  .0027
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, MET206ARG
  
  Bowling et al. (1999) reported a family with 2 consecutive males with
  OTC deficiency (311250), in which the mother had normal biochemical
  studies. OTC genotyping in both brothers showed a met206-to-arg (M206R)
  mutation in exon 6. Genotyping of the mother performed on peripheral
  blood leukocytes and skin fibroblasts showed no mutation, strongly
  suggesting gonadal mosaicism.
  
  .0028
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG40CYS
  
  Ploechl et al. (2001) reported on late-onset OTC deficiency (311250) in
  2 families with mutations in the same codon, but with different base
  substitutions. Onset of symptoms showed great variation, and clinical
  diagnosis was late and difficult. In family A, with a C-T transition
  causing an arg40-to-cys (R40C) substitution in the OTC gene, hemizygous
  males died at ages 12 and 18 years. In family B, with a G-A transition
  causing an arg40-to-his (R40H) substitution (300461.0029), hemizygous
  males died at ages 20, 26, and 30 years. Whereas the R40C mutation is a
  private one, as in most cases of OTC deficiency, the R40H mutation is a
  recurrent one found first by Tuchman et al. (1994), and subsequently by
  Oppliger Leibundgut et al. (1995) and Matsuda et al. (1996).
  
  .0029
  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
  OTC, ARG40HIS
  
  See 300461.0028 and Ploechl et al. (2001).
  
  Mavinakere et al. (2001) used (35)S labeling to study import and
  processing of OTC carrying the R40H mutation in intact CHO cells and in
  isolated rat liver mitochondria compared to wildtype and OTC carrying an
  R141Q mutant that causes complete enzyme deficiency. OTC protein
  carrying the R40H mutation seemed to be imported and processed by the
  mitochondria in a manner similar to that of wildtype. However, it was
  consistently degraded to a smaller fragment in the intact cells, unlike
  the wildtype and R141Q mutant. The mature form of the enzyme was not
  susceptible to degradation. Mavinakere et al. (2001) concluded that
  deficiency in OTC enzymatic function conferred by the R40H mutation is
  likely caused by enhanced degradation of the preprotein in the cytosol.
  The authors further proposed that the variation in the rate of OTC
  turnover is responsible for the heterogeneity of the clinical phenotype
  in patients carrying this mutation.
  
See Also:
  Finkelstein et al. (1989); Fox et al. (1986); Hoogenraad et al. (1983)
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Contributors: 
  Victor A. McKusick - updated: 10/13/2006
  
Creation Date: 
  Cassandra L. Kniffin: 11/26/2003
  
Edit Dates: 
  alopez: 10/13/2006
  carol: 6/3/2004
  tkritzer: 12/11/2003
  carol: 12/4/2003
  ckniffin: 12/4/2003
  
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