GenomeNet

Database: OMIM
Entry: 606933
LinkDB: 606933
MIM Entry: 606933
Title:
  *606933 TYROSINASE; TYR
Text:
  
  DESCRIPTION
  
  Tyrosinase (EC 1.14.18.1) catalyzes the first 2 steps, and at least 1
  subsequent step, in the conversion of tyrosine to melanin (Spritz,
  1994).
  
  CLONING
  
  Kwon et al. (1987) screened a lambda-gt11 human melanocyte cDNA library
  with antibodies against hamster tyrosinase and obtained a partial clone
  for human tyrosinase. The deduced protein lacked the initiating
  methionine, but its first 12 amino acids had characteristics of a signal
  peptide, indicating that the sequence of the mature protein was intact.
  The deduced mature protein contains 548 amino acids and has a calculated
  molecular mass of 62.6 kD. It has 5 glycosylation sites, 2 cysteine-rich
  domains, several histidine-rich sites that may be involved in copper
  binding, and a C-terminal transmembrane domain. RNA blot analysis
  detected an approximately 2.4-kb mRNA in normal and malignant human
  melanocytes, but not in other cell lines tested.
  
  Shibahara et al. (1988) isolated a tyrosinase cDNA from a human melanoma
  cDNA library. The cDNA lacked the 5-prime end, including the initiation
  codon, but it included the full coding sequence for the mature enzyme.
  Shibahara et al. (1988) noted multiple differences between their cDNA
  and the cDNA cloned by Kwon et al. (1987), particularly in the region
  encoding the C terminus. Therefore, Shibahara et al. (1988) isolated a
  genomic clone harboring the 3-prime end of the tyrosinase coding
  sequence, which confirmed the sequence of their cDNA. The deduced mature
  protein contains 511 amino acids and has a calculated molecular mass of
  about 58 kD, similar to the apparent molecular mass of purified
  tyrosinase. It contains 2 evolutionarily conserved copper-binding
  regions and a C-terminal transmembrane domain. Sixteen cysteines and 6
  potential N-glycosylation sites are conserved in mouse and human
  tyrosinase. RNA blot analysis detected a 2.0-kb mRNA in human melanoma
  cells, but not in HeLa cells. Shibahara et al. (1988) presented evidence
  suggesting that tyrosinase is alternatively spliced.
  
  Using a human tyrosinase cDNA clone, Barton et al. (1988) and Kwon et
  al. (1989) isolated mouse tyrosinase genomic clones.
  
  GENE STRUCTURE
  
  Spritz et al. (1988) identified a TaqI RFLP at the TYR locus. The human
  tyrosinase gene contains 4 introns, with exon-intron boundaries
  identical to those in the mouse gene. Giebel and Spritz (1990) reported
  an MboI RFLP in the TYR gene. Giebel et al. (1991) demonstrated that the
  tyrosinase gene contains 5 exons. A tyrosinase-related 'gene,' which
  contains only exons 4 and 5, is located on 11p; see 191270. Ponnazhagan
  et al. (1994) characterized the promoter region.
  
  MAPPING
  
  Kwon et al. (1987) used Southern blot analysis of DNA derived from
  newborn mice carrying lethal albino deletion mutations to show that the
  clone maps near or at the c-albino locus on mouse chromosome 7, which is
  known to be the structural gene for tyrosinase.
  
  Barton et al. (1988) used a human tyrosinase cDNA to map the human TYR
  locus to chromosome 11q14-q21 by Southern blot analysis of somatic cell
  hybrid DNA and by in situ chromosomal hybridization. A second site of
  tyrosinase-related sequences was detected on the short arm of chromosome
  11 near the centromere (p11.2-cen).
  
  GENE FUNCTION
  
  Menkes disease (309400) is an X-linked recessive copper deficiency
  disorder caused by mutations in the ATP7A gene (300011). The ATP7A gene
  encodes a copper-transporting P-type ATPase, which is localized
  predominantly in the trans-Golgi network, but relocates to the plasma
  membrane in cells exposed to elevated copper where it functions in
  copper efflux. Petris et al. (2000) investigated whether the ATP7A
  protein is required for the activity of tyrosinase. Recombinant
  tyrosinase expressed in immortalized Menkes fibroblast cell lines was
  inactive, whereas in normal fibroblasts known to express ATP7A there was
  substantial tyrosinase activity. Coexpression of ATP7A and tyrosinase
  from plasmid constructs in Menkes fibroblasts led to the activation of
  tyrosinase and melanogenesis. This ATP7A-dependent activation of
  tyrosinase was impaired by the chelation of copper in the medium of
  cells and after mutation of the invariant phosphorylation site at
  aspartic acid residue 1044 of ATP7A. The authors proposed that ATP7A
  transports copper into the secretory pathway of mammalian cells to
  activate copper-dependent enzymes.
  
  Setty et al. (2008) showed that the pigment cell-specific cuproenzyme
  tyrosinase acquires copper only transiently and inefficiently within the
  trans-Golgi network of mouse melanocytes. To catalyze melanin synthesis,
  tyrosinase is subsequently reloaded with copper within specialized
  organelles called melanosomes. Copper is supplied to melanosomes by
  ATP7A, a cohort of which localizes to melanosomes in a BLOC1 (biogenesis
  of lysosome-related organelles complex-1)-dependent manner. Setty et al.
  (2008) concluded that cell type-specific localization of a metal
  transporter is required to sustain metallation of an endomembrane
  cuproenzyme, providing a mechanism for exquisite spatial control of
  metalloenzyme activity. Moreover, because BLOC1 subunits are mutated in
  subtypes of the genetic disease Hermansky-Pudlak syndrome (203300),
  these results also show that defects in copper transporter localization
  contribute to hypopigmentation, and hence perhaps other synaptic
  defects, in Hermansky-Pudlak syndrome.
  
  MOLECULAR GENETICS
  
  - Oculocutaneous Albinism
  
  In a child with tyrosinase-negative oculocutaneous albinism (OCA1A;
  203100), Tomita et al. (1989) identified a homozygous 1-bp insertion in
  exon 2 of the TYR gene (606933.0001). The insertion shifted the reading
  frame and introduced a premature termination signal after amino acid
  residue 298, resulting in a truncated enzyme lacking 1 of 2
  copper-binding regions. Functional analysis indicated that the truncated
  tyrosinase was catalytically inactive.
  
  In a patient with classic tyrosinase-negative OCA, Spritz et al. (1989)
  found a thr355-to-lys substitution (606933.0003) that abolished 1 of 6
  putative N-linked glycosylation sites that are completely conserved
  between humans and mice.
  
  In a patient with 'yellow' OCA (see 606952), also called OCA type IB,
  Spritz et al. (1989) identified a pro81-to-leu substitution
  (606933.0002) that may interfere with the normal folding of the
  tyrosinase polypeptide.
  
  On the basis of an analysis of 16 missense mutations, King et al. (1991)
  pointed out that most of the mutations cluster in 4 areas of the gene.
  Two clusters involve the copper A and copper B binding sites and
  mutations in these areas could disrupt the metal ion-protein interaction
  necessary for enzyme function. The other 2 clusters are in exons 1 and 4
  and could indicate important functional domains of the enzyme.
  
  Tripathi et al. (1992) stated that more than 60 independent
  albinism-producing alleles had been described at the TYR locus. They
  reviewed 29 of these and commented on 2 additional novel missense
  substitutions in a 'note added in proof.' They commented that type I OCA
  in Caucasians clearly results from a great variety of different uncommon
  alleles. About 90% of OCA in Caucasians was accounted for by the 29
  mutations they described. More than 80% of the then-known missense
  substitutions clustered within 2 relatively small regions of the
  tyrosinase polypeptide, suggesting that these may represent functionally
  critical sites within the enzyme. Oetting and King (1992) reviewed 17
  reported missense mutations and 10 nonsense and frameshift mutations
  causing tyrosinase-negative OCA and added 2 and 3 new mutations of the
  respective types.
  
  Although a separate locus on chromosome 15 has been identified as the
  site of mutations responsible for tyrosinase-positive OCA, it turns out,
  on the basis of the mutation analyses of Tripathi et al. (1992), that
  some patients clinically defined as 'tyrosinase-positive' OCA (OCA1B;
  203200) in fact have mutations in the tyrosinase gene. Oetting and King
  (1993) tabulated 36 mutations identified in type I OCA: 24 missense, 4
  nonsense, and 8 frameshift mutations. The affected individuals in these
  cases were compound heterozygotes. They also listed 6 polymorphic sites
  useful in haplotype analysis: 2 in the promoter region, 2 in the coding
  region associated with alternative amino acids in the tyrosinase
  protein, and 2 RFLPs in the first intron.
  
  Passmore et al. (1999) reported the mutational profile, determined by
  genetic analysis of the tyrosinase and P (OCA2; 611409) genes, in a
  large German albino population. Of the 74 unrelated patients screened,
  32 (43%) had mutations in the tyrosinase gene, 16 (22%) had P gene
  mutations, and 26 (35%) had no detectable genetic abnormalities. A total
  of 42 distinct mutations were found, of which 19 were novel.
  
  Oetting and King (1999) reviewed mutations and polymorphisms identified
  in the TYR gene in OCA1, the OCA2 gene, the tyrosinase-related protein-1
  gene (TYRP1; 115501) causing OCA3 (203290), the HPS gene in
  Hermansky-Pudlak syndrome (203300), the CHS1 gene in Chediak-Higashi
  syndrome (214500), and the OA1 gene (GPR143; 300808) in X-linked ocular
  albinism (300500). The data was available online from the International
  Albinism Center Albinism Database web site.
  
  - Normal Pigment Variation
  
  Stokowski et al. (2007) demonstrated an association between the TYR SNP
  dbSNP rs1042602 (S192Y; 606933.0008) and skin pigmentation variation
  (SHEP3; 601800) in individuals of South Asian descent.
  
  In a genomewide association study using Icelandic and Dutch population
  samples, Sulem et al. (2007) found an association of the TYR SNP dbSNP
  rs1042602 (S192Y; 606933.0008) with freckling. They also found strong
  correlation (r(2) = 0.86) of the TYR SNP dbSNP rs1393350 with dbSNP
  rs1126809 (R402Q; 606933.0009). The association of the dbSNP rs1393350 A
  allele with blue versus green eye color was close to reaching genomewide
  significance (OR = 1.52, P = 2.0 x 10-(6)), which was confirmed in
  replication samples (combined P = 3.3 x 10(-12)). The authors also
  detected possible secondary associations of this SNP with blond versus
  brown hair and with skin sensitivity to sun.
  
  - Susceptibility to Cutaneous Malignant Melanoma
  
  Gudbjartsson et al. (2008) assessed the effect of gene variants
  affecting hair, eye, and skin pigmentation of Europeans upon the risk of
  cutaneous melanoma (see 601800) and basal cell carcinoma. The authors
  studied 2,121 individuals with cutaneous melanoma and 2,163 individuals
  with basal cell carcinoma, and over 40,000 controls. A 2-SNP haplotype
  near the ASIP gene (600201) was the variant most strongly associated
  with both cutaneous melanoma and basal cell carcinoma. The R402Q variant
  of TYR (606933.0009) showed the second most significant association to
  cutaneous melanoma and basal cell carcinoma.
  
  Bishop et al. (2009) reported a genomewide association study of melanoma
  conducted by the GenoMEL consortium based on 317,000 tagging SNPs for
  1,650 selected cases and 4,336 controls, with replication in an
  additional 2 cohorts (1,149 selected cases and 964 controls from
  GenoMEL, and a population-based case-control study in Leeds of 1,163
  cases and 903 controls). The genomewide screen identified 5 loci with
  genotypes or imputed SNPs reaching P less than 5 x 10(-7). Three of
  these loci were replicated: 16q24 encompassing MC1R (155555) (combined P
  = 2.54 x 10(27) for dbSNP rs258322), 11q14-q21 encompassing TYR (P =
  2.41 x 10(-14) for dbSNP rs1393350), and 9p21 adjacent to MTAP (156540)
  and flanking CDKN2A (600160) (P = 4.03 x 10(-7) for dbSNP rs7023329)
  (see 155601). MC1R and TYR are associated with pigmentation, freckling,
  and cutaneous sun sensitivity, well-recognized melanoma risk factors.
  Bishop et al. (2009) concluded that despite wide variation in allele
  frequency, these genetic variants show notable homogeneity of effect
  across populations of European ancestry living at different latitudes
  and show independent association to disease risk.
  
  - Other Disease Associations
  
  For a discussion of a possible association between variation in the TYR
  gene and susceptibility to vitiligo, see 193200.
  
  POPULATION GENETICS
  
  Giebel and Spritz (1990) estimated that the frequencies of alleles A1
  and A2 were 0.48 and 0.52, respectively.
  
  ANIMAL MODEL
  
  A mutation in tyrosinase responsible for the albino mouse appears to be
  a change of cysteine-85 to serine (Kwon et al., 1988), resulting from a
  change of guanine 390 to cytosine. Jackson and Bennett (1990) studied
  revertant cells and found that loss of the mutant allele was
  responsible.
  
  The zebrafish albino mutant 'sdy' is caused by mutation in the 'sandy'
  gene. Page-McCaw et al. (2004) cloned the sandy gene and determined that
  it encodes tyrosinase. In a complex series of experiments, the authors
  found that sdy mutants demonstrated impaired optokinetic behavior after
  a return to bright light after periods of darkness compared to wildtype.
  The sdy mutation compromised the ability of retinal circuits to reset
  sensitivity to light. The deficit was demonstrated in fully pigmented
  fish by inhibiting tyrosinase, indicating that the response in sdy fish
  was not due to the absence of melanin. The findings suggested that a
  tyrosinase product other than melanin was responsible, and Page-McCaw et
  al. (2004) hypothesized that the product could be dopamine.
  
  Schmidt-Kuntzel et al. (2005) found that 2 nonsynonymous substitutions
  in the Tyr gene caused the 'siamese' and 'burmese' alleles of the albino
  locus, respectively, in domestic cats.
  
Allelic Variants:
  .0001
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, 1-BP INS, 1012C
  
  In a child with tyrosinase-negative oculocutaneous albinism (203100),
  Tomita et al. (1989) identified a homozygous 1-bp insertion (C) between
  nucleotides 1011 and 1012 in exon 2 of the TYR gene. The insertion
  shifted the reading frame and introduced a premature termination signal
  (TGA codon) after amino acid residue 298, resulting in a truncated
  enzyme lacking 1 of 2 copper-binding regions. Functional analysis
  indicated that the truncated tyrosinase was catalytically inactive. Both
  parents and 1 sib were heterozygous; their DNAs reacted with both the
  mutant probe and the normal probe.
  
  .0002
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  ALBINISM, OCULOCUTANEOUS, TYPE IB, INCLUDED
  TYR, PRO81LEU
  
  In 6 of 30 unrelated patients with a tyrosinase-negative (type IA)
  oculocutaneous albinism (203100), Giebel et al. (1990) observed a
  CCT-to-CTT change in codon 81 resulting in a substitution of leucine for
  proline. The codon 81 substitution abolished an HaeIII restriction site
  within exon 1, thus permitting rapid screening for the substitution by
  PCR amplification of exon 1 followed by HaeIII cleavage. Giebel et al.
  (1990) detected the codon 81 mutation in 4 of 15 independently
  ascertained type I OCA probands; of their 30 OCA tyrosinase alleles, 6
  contained the codon 81 mutation, yielding an overall frequency of 0.2
  for this allele among these type I OCA probands. Giebel et al. (1991)
  found the pro81-to-leu mutation in compound heterozygosity in a family
  with type IB ('yellow') OCA (606952). The other allele was the
  val275-to-phe mutation (606933.0007).
  
  .0003
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, THR355LYS
  
  In a woman with classic albinism (203100), Spritz et al. (1990)
  demonstrated compound heterozygosity for 2 allelic single-base missense
  substitutions in the tyrosinase gene that altered codons 355
  (thr-to-lys) and 365 (asp-to-asn). These substitutions would be expected
  to cause a severe defect of tyrosinase activity. Both result in changes
  of net charge, and both occur in a region of predicted helical structure
  within the so-called copper-binding region of the enzyme. In another
  numbering system, this is referred to as THR373LYS (King et al., 1991).
  In a case of type IA oculocutaneous albinism, Oetting et al. (1991)
  identified a change from ACA to AAA in codon 373 resulting in
  substitution of lysine for threonine. Also see Tripathi et al. (1992).
  
  .0004
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ASP365ASN
  
  This mutation was found by Spritz et al. (1990); see 606933.0003. In
  another numbering system this is referred to as ASP383ASN (King et al.,
  1991).
  
  .0005
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ARG77GLN
  
  By enzymatic DNA amplification and direct DNA sequencing, Kikuchi et al.
  (1990) demonstrated a G-to-A change in nucleotide 309. This was thought
  to result in a change of arginine-77 to glutamine. Also see Tripathi et
  al. (1992).
  
  .0006
  ALBINISM, OCULOCUTANEOUS, TYPE IB
  TYR, PRO406LEU
  
  In an Amish kindred with oculocutaneous albinism (606952) reported by
  Nance et al. (1970), Giebel et al. (1990) observed a substitution of
  leucine for proline at position 406 of the tyrosinase gene. Tripathi et
  al. (1992) stated that this mutation had been found only among the
  Amish.
  
  .0007
  ALBINISM, OCULOCUTANEOUS, TYPE IB
  TYR, VAL275PHE
  
  In a patient with the 'yellow' form of oculocutaneous albinism (type IB)
  (606952), Giebel et al. (1990) found compound heterozygosity for the
  pro81-to-leu mutation (606933.0002) and a novel val275-to-phe mutation.
  
  .0008
  SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN
  SKIN/HAIR/EYE PIGMENTATION 3, FRECKLING, INCLUDED
  TYR, SER192TYR, (dbSNP rs1042602)
  
  Spritz et al. (1990) noted that serine versus tyrosine at position 192
  of tyrosinase is a common nonpathologic polymorphism.
  
  In a genomewide association study of skin pigmentation variation
  (601800) using 1,620,742 SNPs in a population of 737 individuals of
  South Asian ancestry living in the United Kingdom, Stokowski et al.
  (2007) found association of the TYR SNP dbSNP rs1042602 (S192Y) with
  skin pigmentation. The association was replicated in a second
  independent cohort of 235 individuals.
  
  In a discovery sample of 2,986 Icelanders and replication samples of
  2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found an
  association of the TYR SNP dbSNP rs1042602 with freckling (discovery OR
  = 1.32, P = 1.5 x 10(-11)). No association was found between this SNP
  and skin or eye color. Based on analysis of HapMap samples, the A allele
  of dbSNP rs1042602, associated with the absence of freckles, is found at
  a frequency of approximately 35% in European populations, while the
  ancestral C allele is fixed in Asian and Nigerian Yoruba populations.
  There was evidence that the A allele has been subject to positive
  selection in European populations.
  
  .0009
  ALBINISM, OCULOCUTANEOUS, TYPE IB
  WAARDENBURG SYNDROME 2 AND OCULAR ALBINISM, DIGENIC, INCLUDED;;
  ALBINISM, OCULOCUTANEOUS TYPE I, TEMPERATURE-SENSITIVE, INCLUDED;;
  MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 8, INCLUDED;;
  SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN, INCLUDED;;
  SKIN/HAIR/EYE PIGMENTATION 3, BLUE/GREEN EYES, INCLUDED
  TYR, ARG402GLN, (dbSNP rs1126809)
  
  Hutton and Spritz (2008) noted that the dbSNP rs1126809 variant encodes
  a tyrosinase enzyme with an arg402-to-gln (R402Q) substitution,
  resulting in a tyrosinase peptide that is thermolabile and subject to
  endoplasmic reticulum retention, yielding only 25% of the catalytic
  activity of the wildtype enzyme at 37 degrees C. The SNP is quite common
  among Caucasians, with an allele frequency of approximately 0.278.
  Oetting et al. (2009) noted that the allele frequency is much lower in
  African Americans (0.05) and absent in the Asian population.
  
  Oculocutaneous Albinism Type IB
  
  Fukai et al. (1995) showed that a mild form of OCA1B (606952) with only
  ocular albinism can result from compound heterozygosity for a mutant
  allele of TYR and the polymorphic R402Q allele. This polymorphic allele
  encodes a form of tyrosinase with reduced catalytic activity.
  
  Chiang et al. (2008) reported a Hispanic family in which 2 sibs had
  variable manifestations of OCA1B. A 6-year-old boy had nystagmus,
  decreased vision, light hair, light skin color, and foveal hypoplasia.
  His sister had exotropia, blonde hair, light skin color, and brown
  irides with no history of nystagmus, foveal hypoplasia or decreased
  vision. Genetic analysis identified compound heterozygosity for 2
  variants in the TYR gene: G47D (606933.0024) and the hypomorphic allele
  R402Q. Each unaffected parent was heterozygous for 1 of the variants.
  Chiang et al. (2008) postulated that the clinical spectrum of OCA
  depends on a pigmentation threshold of the affected individual, and that
  OCA is a quantitative trait disorder with phenotypic variation in
  individuals of different ethnic backgrounds.
  
  In 36 unrelated Caucasian patients with a clinical diagnosis of
  autosomal recessive ocular albinism (AROA), Hutton and Spritz (2008)
  identified 20 patients who were compound heterozygous for the R402Q
  variant on 1 allele and for various severe OCA1 mutations on the other
  allele. The authors noted that this genotypic combination should occur
  in approximately 1 per 280 Caucasian individuals; however, the
  prevalence of AROA, while unknown, is certainly lower than that,
  indicating that the penetrance of the AROA phenotype must be very low,
  given a susceptible genotype.
  
  After excluding black and Asian OCA1 patients, Chiang et al. (2009)
  identified 23 OCA patients in their database with 1 or 2 TYR mutations.
  The authors found that 10 of the 11 patients with only 1 TYR mutation
  were heterozygous for the R402Q allele, whereas among the 12 patients
  with 2 mutations in TYR, 2 were heterozygous and 1 homozygous for R402Q,
  and 9 did not carry the R402Q allele. Chiang et al. (2009) concluded
  that the R402Q allele is strongly associated with albinism patients who
  have only 1 mutation in TYR.
  
  Oetting et al. (2009) analyzed the segregation of the Q402 allele in 12
  families with oculocutaneous albinism type I in which all parents were
  unaffected with normal visual acuity. In 9 families, 1 parent in each
  sibship had a pathologic mutation on 1 allele and the Q402 allele in
  trans, yet none had hypopigmentation or the presence of abnormal visual
  acuity and fovial hypoplasia. In the remaining 3 families, 2 of which
  were previously studied by Hutton and Spritz (2008), the maternal
  mutation was not identified: in 1 family, the unaffected mother was
  homozygous for Q402 and also presumably carried an unidentified
  pathologic mutation; in another, the normal father had a pathologic
  mutation on 1 allele and Q402 in trans; and in the last family, the
  unaffected mother carried R402 on the allele presumably containing an
  unidentified mutation that was passed to her child, and Q402 in trans on
  the untransmitted allele. Oetting et al. (2009) concluded that the R402Q
  variant of TYR is not associated with autosomal recessive ocular
  albinism (AROA) but suggested that a causative variant may be in genetic
  disequilibrium with the R402Q variant.
  
  Waardenburg Syndrome 2 and Ocular Albinism
  
  Morell et al. (1997) found that the family reported by Bard (1978) with
  a combination of congenital deafness and ocular albinism had a syndrome
  apparently due to digenic inheritance. Affected individuals had features
  consistent with Waardenburg syndrome type 2 and ocular albinism; they
  were heterozygous for a 1-bp deletion in the MITF gene (156845.0005) and
  homozygous or heterozygous for the R402Q mutation. The transcription
  factor MITF regulates the expression of the TYR gene.
  
  Temperature-Sensitive Oculocutaneous Albinism
  
  In an unusual subset of oculocutaneous albinism type I, designated
  OCA1-TS (see 606952), mutations in the TYR gene render tyrosinase
  temperature-sensitive (ts). Consequently, melanin synthesis occurs only
  in cooler areas of the body, such as the arms and legs. The resultant
  pattern of peripheral pigmentation is analogous to that of the Siamese
  cat and the Himalayan mouse. Both the R402Q variant and the similar but
  less prevalent R422Q variant (606933.0012) are temperature-sensitive.
  The R402Q variant represents approximately 15% of the gene pool among
  Caucasians (King et al., 1991). Berson et al. (2000) analyzed the
  localization and processing of the R402Q variant and showed that the ts
  phenotype is due to a defect in protein folding that prevents exit from
  the endoplasmic reticulum (ER). The partial ts phenotype of a wildtype
  allelic form of tyrosinase and the lack of an apparent significant
  increase in ER-associated degradation of the R402Q variant suggested
  that it exaggerates an inefficient folding process inherent in human
  tyrosinase when expressed in nonmelanogenic cells.
  
  Variation in Skin/Hair/Eye Pigmentation
  
  In a genomewide association study using Icelandic and Dutch population
  samples, Sulem et al. (2007) found an association of the TYR SNP dbSNP
  rs1042602 (S192Y; 606933.0008) with freckling (SHEP3; 601800). They also
  found strong correlation (r(2) = 0.86) of the TYR SNP dbSNP rs1393350
  with the TYR SNP dbSNP rs1126809 (R402Q). Sulem et al. (2008) presented
  results from a genomewide association study for variants associated with
  human pigmentation characteristics among 5,130 Icelanders, with
  follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. The
  dbSNP rs1126809 R402Q variant showed genomewide significance for
  association with skin sensitivity to sun (p = 7.1 x 10(-13)) and blue
  versus green eye color (p = 4.6 x 10(-21)).
  
  Susceptibility to Cutaneous Malignant Melanoma
  
  In a study of the effect of pigmentation-associated genetic sequence
  variants on risk of cutaneous melanoma (see 601800) and basal cell
  carcinoma, Gudbjartsson et al. (2008) found that the R402Q variant of
  TYR, previously shown to affect eye color and tanning response,
  conferred risk of cutaneous melanoma (odds ratio = 1.21, P = 2.8 x
  10(-7)) and basal cell carcinoma (odds ratio = 1.14, P = 6.1 x 10(-4)).
  
  .0010
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ARG59GLN
  
  In a case of tyrosinase-negative oculocutaneous albinism (203100),
  Takeda et al. (1990) found a G-to-A transition at nucleotide 312 in exon
  1 causing an arg(CGG)-to-gln(CAG) substitution at amino acid 59. The
  base change eliminated 1 MspI site and created a new BstNI site valuable
  for screening other OCA patients and heterozygous carriers. The patient
  was homozygous for the arg59-to-gln mutation. Heterozygotes in the
  family were phenotypically normal. Transfection of the mutant gene
  failed to give rise to detectable tyrosinase activity in transient
  expression assays.
  
  .0011
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, CYS89ARG
  
  In an American black with classic, tyrosinase-negative oculocutaneous
  albinism (203100), Spritz et al. (1991) identified substitution of
  arginine for cysteine at codon 89. The subject was homozygous for a
  TGC-to-CGC transition.
  
  .0012
  ALBINISM, OCULOCUTANEOUS TYPE I, TEMPERATURE-SENSITIVE
  TYR, ARG422GLN
  
  King et al. (1989, 1991) described a temperature-sensitive abnormality
  of tyrosinase resulting in oculocutaneous albinism (606952). At age 29
  years, the proband showed white axillary hair, scalp hair that was white
  with a yellow tint, pubic hair that was dark yellow to light brown, hair
  on the arm that was reddish blond, and hair on the leg that was dark
  brown. No ocular pigment was present. Analysis of the pedigree suggested
  that the index case and her similarly affected brother were genetic
  compounds. This is the human equivalent of the temperature-related forms
  of albinism seen in the Siamese cat and the Himalayan mouse. Giebel et
  al. (1991) reported the Himalayan phenomenon in humans, i.e., peripheral
  pigmentation in oculocutaneous albinism associated with
  temperature-sensitive tyrosinase. In a patient with type I OCA in which
  hypopigmentation was related to local body temperature, Giebel et al.
  (1991) found that CGG (arg) at codon 422 in tyrosinase was converted to
  CAG (gln). The proband and her 2 affected brothers completely lacked
  melanin pigment at birth but after puberty developed slight pigmentation
  of facial and pubic hair and extensive pigmentation in relatively cool
  parts such as the hair of the arms and legs. Kwon et al. (1989) showed
  that the temperature-sensitive tyrosinase in the Himalayan mouse is due
  to a his420-to-arg mutation, only 2 amino acids away from the human
  codon 422 substitution described by Giebel et al. (1991). By in vitro
  mutagenesis and introduction of the codon 422 mutation into HeLa cells,
  Giebel et al. (1991) demonstrated that the codon 422 substitution
  resulted in thermosensitivity of tyrosinase; tyrosinase activity was 28%
  of normal in cells cultured at 31 degrees C and only 1.4% of normal in
  cells cultured at 37 degrees C.
  
  .0013
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, -199C-A
  
  Oetting and King (1991) reported a mutation in the CCAAT box associated
  with tyrosinase-negative OCA (203100). The proband was a genetic
  compound: one allele had a C-to-A substitution at -199 that changed
  CCAATTC to CCAATTA. The other chromosome carried a G-to-A substitution
  in codon 55 of exon 1, changing a cysteine to tyrosine.
  
  .0014
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, TRP178TER
  
  In 2 sibs of Afghan ethnic origin, offspring of first-cousin parents,
  Giebel et al. (1991) found an amber nonsense mutation at codon 178 which
  converted tryptophan to stop.
  
  .0015
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, GLY191ASP
  
  In 2 unrelated patients with type IA oculocutaneous albinism (203100),
  Oetting et al. (1991) found deletion of a guanine from codon 191 causing
  substitution of asparagine for glycine and resulting in a frameshift and
  a premature termination signal at codon 225.
  
  .0016
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ASN382LYS
  
  In a case of type IA oculocutaneous albinism (203100), Oetting et al.
  (1991) found a change in codon 382 from AAC to AAA resulting in
  substitution of lysine for asparagine.
  
  .0017
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, 2-BP DEL, TG, CODONS 244,245
  
  In a case of type IA oculocutaneous albinism (203100), Oetting et al.
  (1991) found deletion of a TG dinucleotide from codons 244 and 245
  converting TGTGAC to TGAC and leading to premature termination at the
  TGA signal.
  
  .0018
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, MET96ASN
  
  In a case of type IA oculocutaneous albinism (203100), Oetting et al.
  (1991) found a change in codon 96 from ATG (met) to AAT (asn) due to the
  insertion of an adenine. This caused a frameshift and a premature
  termination signal at codon 168.
  
  .0019
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ASP42GLY
  
  In a patient with type IA OCA (203100), King et al. (1991) found a
  GAC-to-GGC change at codon 42 resulting in substitution of glycine for
  aspartic acid. See Tripathi et al. (1992) for the GAC(asp)-to-GGC(gly)
  mutation at codon 42.
  
  .0020
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, CYS55TYR
  
  In a patient with type IA OCA (203100), King et al. (1991) found a
  TGT-to-TAT change at codon 55 resulting in substitution of tyrosine for
  cysteine.
  
  .0021
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ALA206THR
  
  In a patient with type IA OCA (203100), King et al. (1991) found a
  GCT-to-ACT change at codon 206 resulting in substitution of threonine
  for alanine.
  
  .0022
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, GLY419ARG
  
  In a patient with type IA OCA (203100), King et al. (1991) found a
  GGA-to-AGA change at codon 419 resulting in substitution of arginine for
  glycine.
  
  .0023
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, PRO21SER
  
  See Tripathi et al. (1992) for the CCT(pro)-to-TCT(ser) mutation at
  codon 21.
  
  .0024
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  ALBINISM, OCULOCUTANEOUS, TYPE IB, INCLUDED
  TYR, GLY47ASP
  
  See Tripathi et al. (1992) for the GGC(gly)-to-GAC(asp) mutation at
  codon 47. Oetting et al. (1993) found this mutation to be frequent among
  albinos in Puerto Rico. They found the G47D mutation in homozygous state
  in 9 of 12 unrelated Puerto Ricans with type IA oculocutaneous albinism
  (203100). Two other individuals were heterozygous for the mutation; 1 of
  these had the T373K mutation (606933.0003) in the homologous allele. One
  of the individuals with Negroid features was homozygous for a W236X
  mutation (606933.0035). Because of the migration between Puerto Rico and
  the Canary Islands, 3 persons with OCA from the Canary Islands were
  analyzed. One was a genetic compound for the G47D mutation and a novel
  L216M mutation (606933.0036), one was homozygous for the P81L mutation
  (606933.0002), and one was heterozygous for the P81L mutation. Haplotype
  analysis in the Puerto Rican cases showed that the G47D mutation
  occurred on a single haplotype, consistent with a common ancestor for
  all individuals having this mutation. Two different haplotypes were
  found associated with the P81L mutation, suggesting that this may be
  either a recurring mutation for the tyrosinase gene or a recombination
  between haplotypes.
  
  Chiang et al. (2008) reported a Hispanic family in which 2 sibs had
  variable manifestations of OCA1B (606952). A 6-year-old boy had
  nystagmus, decreased vision, light hair, light skin color, and foveal
  hypoplasia. His sister had exotropia, blonde hair, light skin color, and
  brown irides with no history of nystagmus, foveal hypoplasia or
  decreased vision. Genetic analysis identified compound heterozygosity
  for 2 variants in the TYR gene: G47D and the hypomorphic allele R402Q
  (606933.0009). Each unaffected parent was heterozygous for 1 of the
  variants. Chiang et al. (2008) postulated that the clinical spectrum of
  OCA depends on a pigmentation threshold of the affected individual, and
  that OCA is a quantitative trait disorder with phenotypic variation in
  individuals of different ethnic backgrounds.
  
  .0025
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ARG217TRP
  
  See Tripathi et al. (1992) for the CGG(arg)-to-TGG(trp) mutation at
  codon 217.
  
  .0026
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ARG299HIS
  
  See Tripathi et al. (1992) for the CGT(arg)-to-CAT(his) mutation at
  codon 299.
  
  .0027
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, 1-BP INS, C, CODON 310
  
  See Tripathi et al. (1992) for the frameshift mutation in codon 310,
  converting CCA (pro) to CCCA.
  
  .0028
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ASN371THR
  
  Tripathi et al. (1992) described an AAT-to-ACT transversion converting
  asparagine-371 to threonine.
  
  .0029
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, 1-BP DEL, T, CODON 388
  
  See Tripathi et al. (1992) for the 1-bp deletion in codon 388 (CTT to
  CT) creating a frameshift.
  
  .0030
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ARG403SER
  
  See Tripathi et al. (1992) for the AGG (arg)-to-AGT (ser) mutation in
  codon 403.
  
  .0031
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, GLY446SER
  
  See Tripathi et al. (1992) for the GGC(gly)-to-AGC(ser) mutation in
  codon 446.
  
  .0032
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, ASP448ASN
  
  See Tripathi et al. (1992) for the GAC(asp)-to-AAC(asn) mutation in
  codon 448.
  
  .0033
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, THR489FS, 1-BP INS
  
  See Tripathi et al. (1992) for the 1-bp insertion converting codon 489
  from ACT(thr) to ACTT and creating a frameshift.
  
  .0034
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, 1-BP INS, C, CODON 501
  
  See Tripathi et al. (1992) for the 1-bp insertion converting codon 501
  from CGT(arg) to CCGT and creating a frameshift.
  
  .0035
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, TRP236TER
  
  Among 12 unrelated Puerto Rican individuals with OCA IA (203100) in
  Puerto Rico, Oetting et al. (1993) found that 1 who had Negroid features
  was homozygous for a nonsense mutation: W236X.
  
  .0036
  ALBINISM, OCULOCUTANEOUS, TYPE IA
  TYR, LEU216MET
  
  Oetting et al. (1993) found that 1 of 3 individuals with OCA (203100)
  from the Canary Islands was a genetic compound for the G47D mutation
  (606933.0024) and for a novel missense mutation, L216M.
  
  .0037
  ALBINISM, OCULOCUTANEOUS, TYPE IB
  TYR, MET1VAL
  
  In an analysis of 12 unrelated patients with autosomal recessive
  oculocutaneous albinism type IB (606952), Fukai et al. (1995) found 2
  patients that had abnormalities of the tyrosinase gene. Each was a
  compound heterozygote for a different pathologic mutant allele and an
  allele containing a 'normal' polymorphism, arg402-to-gln (606933.0009),
  which resulted in a tyrosinase polypeptide with reduced thermal
  stability. These patients had a clinically mild form of OCA1B, with a
  fixed visual deficit resulting from low tyrosinase activity during fetal
  development but with normal pigmentation of the skin and hair
  postnatally. The pathologic mutation in 1 of the patients was cys55 to
  tyr (606933.0020). The second patient was heterozygous for a novel
  missense substitution involving the translational initiation codon, met1
  to val (ATG to GTG).
  
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Contributors: 
  Matthew B. Gross - updated: 12/9/2010
  Marla J. F. O'Neill - updated: 8/27/2010
  Marla J. F. O'Neill - updated: 12/4/2009
  Marla J. F. O'Neill - updated: 10/30/2009
  Ada Hamosh - updated: 9/16/2009
  Cassandra L. Kniffin - updated: 3/3/2009
  Ada Hamosh - updated: 9/24/2008
  Ada Hamosh - updated: 8/6/2008
  Victor A. McKusick - updated: 12/28/2007
  Victor A. McKusick - updated: 12/12/2007
  Patricia A. Hartz - updated: 12/13/2005
  Cassandra L. Kniffin - updated: 2/8/2005
  Victor A. McKusick - updated: 3/5/2003
  
Creation Date: 
  Cassandra L. Kniffin: 5/13/2002
  
Edit Dates: 
  carol: 02/02/2011
  mgross: 12/9/2010
  wwang: 9/2/2010
  terry: 8/27/2010
  wwang: 5/24/2010
  ckniffin: 5/21/2010
  carol: 12/23/2009
  terry: 12/4/2009
  mgross: 11/9/2009
  wwang: 10/30/2009
  terry: 10/30/2009
  alopez: 10/20/2009
  terry: 9/16/2009
  wwang: 9/2/2009
  wwang: 3/10/2009
  ckniffin: 3/3/2009
  alopez: 9/26/2008
  terry: 9/24/2008
  alopez: 9/4/2008
  terry: 8/6/2008
  alopez: 1/17/2008
  alopez: 1/16/2008
  terry: 12/28/2007
  alopez: 12/12/2007
  carol: 9/13/2007
  ckniffin: 9/13/2007
  carol: 9/12/2007
  ckniffin: 9/11/2007
  wwang: 12/20/2005
  wwang: 12/13/2005
  ckniffin: 2/8/2005
  carol: 11/5/2003
  carol: 3/28/2003
  ckniffin: 3/21/2003
  carol: 3/19/2003
  tkritzer: 3/11/2003
  terry: 3/5/2003
  carol: 5/29/2002
  carol: 5/15/2002
  ckniffin: 5/15/2002
  
OMIM
DBGET integrated database retrieval system