HGNC Approved Gene Symbol: TYR
SNOMEDCT: 6483008, 82342003; ICD10CM: E70.320;
Cytogenetic location: 11q14.3 Genomic coordinates (GRCh38) : 11:89,177,875-89,295,759 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q14.3 | [Skin/hair/eye pigmentation 3, blue/green eyes] | 601800 | Autosomal dominant | 3 |
| [Skin/hair/eye pigmentation 3, light/dark/freckling skin] | 601800 | Autosomal dominant | 3 | |
| {Melanoma, cutaneous malignant, susceptibility to, 8} | 601800 | Autosomal dominant | 3 | |
| Albinism, oculocutaneous, type IA | 203100 | Autosomal recessive | 3 | |
| Albinism, oculocutaneous, type IB | 606952 | Autosomal recessive | 3 |
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).
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.
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.
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).
Petris et al. (2000) investigated whether tyrosinase activity required the copper-transporting P-type ATPase ATP7A (300011). Recombinant tyrosinase was inactive when expressed in immortalized fibroblasts from patients with Menkes disease (309400), a recessive copper deficiency disorder caused by mutations in ATP7A. In contrast, normal fibroblasts that expressed ATP7A showed substantial tyrosinase activity. Coexpression of ATP7A and tyrosinase from plasmid constructs in Menkes fibroblasts led to activation of tyrosinase and melanogenesis. This ATP7A-dependent activation of tyrosinase was impaired by chelation of copper in the medium of cells and after mutation of the invariant phosphorylation site at asp1044 of ATP7A. The authors proposed that ATP7A transports copper into the secretory pathway of mammalian cells to activate copper-dependent enzymes, including tyrosinase.
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.
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 in the TYR gene (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, also known as OCA type IB (OCA1B; 606952), Spritz et al. (1989) identified a pro81-to-leu substitution in the TYR gene (606933.0002) that may interfere with the normal folding of the tyrosinase polypeptide.
In 6 of 30 unrelated patients with OCA1A, Giebel et al. (1990) identified the P81L substitution in the TYR gene. Giebel et al. (1990) also identified mutations in the TYR gene in patients with OCA1B (see, e.g., 606933.0006 and 606933.0007).
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 were 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 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 rs1042602 (S192Y; 606933.0008) with freckling. They also found strong correlation (r(2) = 0.86) of the TYR SNP rs1393350 with rs1126809 (R402Q; 606933.0009). The association of the 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 rs258322), 11q14-q21 encompassing TYR (p = 2.41 x 10(-14) for rs1393350), and 9p21 adjacent to MTAP (156540) and flanking CDKN2A (600160) (p = 4.03 x 10(-7) for 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 606579.
Giebel and Spritz (1990) estimated that the frequencies of alleles A1 and A2 were 0.48 and 0.52, respectively.
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.
Polanowski et al. (2012) analyzed sequence variation in exon 1 of the Tyr gene in 66 humpback whale (Megaptera novaeangliae) samples, including that of a white humpback whale known as 'Migaloo.' They determined that Migaloo was homozygous for a cytosine deletion (264delC) at codon 88, predicted to result in a frameshift and premature termination of the protein. The truncated protein would lack both of the putative copper-binding sites and the putative transmembrane segment and would therefore have no tyrosinase enzymatic activity. The authors noted that although Migaloo's eye was not visible in any photographs, an unusual amount of pink pigmentation around his blowhole could be seen.
In a child with tyrosinase-negative oculocutaneous albinism (OCA1A; 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.
Oculocutaneous Albinism, Type 1B
In a patient with 'yellow' OCA (OCA1B; 606952), Spritz et al. (1989) identified a pro81-to-leu (P81L) substitution that was predicted to interfere with the normal folding of the tyrosinase polypeptide.
Oculocutaneous Albinism, Type 1A
In 6 of 30 unrelated patients with a tyrosinase-negative (type IA) oculocutaneous albinism (OCA1A; 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 OCA. The other allele was the val275-to-phe mutation (606933.0007).
In a woman with classic albinism (OCA1A; 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).
For discussion of an asp365-to-asn (D365N) mutation in the TYR gene that was found in compound heterozygous state in a patient with oculocutaneous albinism 1A (OCA1A; 203100) by Spritz et al. (1990), see 606933.0003. In another numbering system this is referred to as ASP383ASN (King et al., 1991).
In a Japanese patient with oculocutaneous albinism 1A (OCA1A; 203100), Kikuchi et al. (1990) demonstrated a G-to-A change in nucleotide 309 of the TYR gene by enzymatic DNA amplification and direct DNA sequencing. This was thought to result in a change of arginine-77 to glutamine. Also see Tripathi et al. (1992).
In an Amish kindred with oculocutaneous albinism (OCA1B; 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.
In a patient with the 'yellow' form of oculocutaneous albinism (type IB) (OCA1B; 606952), Giebel et al. (1990) found compound heterozygosity for the pro81-to-leu mutation (606933.0002) and a novel val275-to-phe mutation.
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 (SHEP3; 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 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 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 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.
Hutton and Spritz (2008) noted that the 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 oculocutaneous albinism 1B (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.
In 31 Caucasian patients with 1 or 2 mutations in the TYR gene, Simeonov et al. (2013) found that the R402Q allele was more frequent in the group with 1 mutation (50%) compared to the group with 2 mutations (10%). In 5 patients with no mutation in TYR who did not have paired trans-mutation in another OCA gene, they found that 40% of alleles had R402Q.
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 (WS2A; 193510) 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 rs1042602 (S192Y; 606933.0008) with freckling (SHEP3; 601800). They also found strong correlation (r(2) = 0.86) of the TYR SNP rs1393350 with the TYR SNP 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 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)).
In a case of tyrosinase-negative oculocutaneous albinism (OCA1A; 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.
In an American black with classic, tyrosinase-negative oculocutaneous albinism (OCA1A; 203100), Spritz et al. (1991) identified substitution of arginine for cysteine at codon 89. The subject was homozygous for a TGC-to-CGC transition.
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.
This variant, formerly titled ALBINISM, OCULOCUTANEOUS, TYPE IA, has been reclassified as a polymorphism based on the report by Oetting and King (1993).
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. Subsequently, Oetting and King (1993) determined that this variant is a polymorphism in all racial groups.
In 2 sibs of Afghan ethnic origin, offspring of first-cousin parents, with oculocutaneous albinism (OCA1A; 203100), Giebel et al. (1991) found an amber nonsense mutation at codon 178 which converted tryptophan to stop.
In 2 unrelated patients with type IA oculocutaneous albinism (OCA1A; 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.
In a case of type IA oculocutaneous albinism (OCA1A; 203100), Oetting et al. (1991) found a change in codon 382 from AAC to AAA resulting in substitution of lysine for asparagine.
In a case of type IA oculocutaneous albinism (OCA1A; 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.
In a case of type IA oculocutaneous albinism (OCA1A; 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.
In a patient with type IA OCA (OCA1A; 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.
In a patient with type IA OCA (OCA1A; 203100), King et al. (1991) found a TGT-to-TAT change at codon 55 resulting in substitution of tyrosine for cysteine.
In a patient with type IA OCA (OCA1A; 203100), King et al. (1991) found a GCT-to-ACT change at codon 206 resulting in substitution of threonine for alanine.
In a patient with type IA OCA (OCA1A; 203100), King et al. (1991) found a GGA-to-AGA change at codon 419 resulting in substitution of arginine for glycine.
In a Caucasian girl with type IA OCA (OCA1A; 203100) Tripathi et al. (1992) identified a CCT(pro)-to-TCT(ser) mutation at codon 21 of the TYR gene, resulting in a pro21-to-ser (P21S) substitution. The P21S mutation was found in compound heterozygosity with a 1-bp deletion (CTT to CT) (606933.0029) in codon 388, which created a frameshift.
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 (OCA1A; 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.
See Tripathi et al. (1992) for the CGG(arg)-to-TGG(trp) mutation at codon 217 found in patients with oculocutaneous albinism type 1A (OCA1A; 203100).
See Tripathi et al. (1992) for the CGT(arg)-to-CAT(his) mutation at codon 299 found in patients with oculocutaneous albinism type 1A (OCA1A; 203100).
See Tripathi et al. (1992) for the frameshift mutation in codon 310, converting CCA (pro) to CCCA, in patients with oculocutaneous albinism type 1A (OCA1A; 203100).
Tripathi et al. (1992) described an AAT-to-ACT transversion converting asparagine-371 to threonine found in patients with oculocutaneous albinism type 1A (OCA1A; 203100).
For discussion of a 1-bp deletion in codon 388 of the TYR gene that was found in compound heterozygous state in a patient with oculocutaneous albinism type 1A (OCA1A; 203100) by Tripathi et al. (1992), see 203100.0023.
See Tripathi et al. (1992) for the AGG (arg)-to-AGT (ser) mutation in codon 403.
See Tripathi et al. (1992) for the GGC(gly)-to-AGC(ser) mutation in codon 446.
See Tripathi et al. (1992) for the GAC(asp)-to-AAC(asn) mutation in codon 448.
See Tripathi et al. (1992) for the 1-bp insertion converting codon 489 from ACT(thr) to ACTT and creating a frameshift.
See Tripathi et al. (1992) for the 1-bp insertion converting codon 501 from CGT(arg) to CCGT and creating a frameshift.
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.
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.
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).
Among 1,281 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) identified 180 heterozygotes and 3 homozygotes for a G-to-A transition at nucleotide 272 of the TYR gene, resulting in a cys-to-tyr substitution at codon 91 (C91Y). The C91Y mutation resulting in oculocutaneous albinism type IA (203100) was determined to be a private mutation among the Hutterites with a carrier frequency of 0.141, or 1 in 7.
Bard, L. A. Heterogeneity in Waardenburg's syndrome: report of a family with ocular albinism. Arch. Ophthal. 96: 1193-1198, 1978. [PubMed: 666627] [Full Text: https://doi.org/10.1001/archopht.1978.03910060027006]
Barton, D. E., Kwon, B. S., Francke, U. Human tyrosinase gene, mapped to chromosome 11 (q14-q21), defines second region of homology with mouse chromosome 7. Genomics 3: 17-24, 1988. [PubMed: 3146546] [Full Text: https://doi.org/10.1016/0888-7543(88)90153-x]
Berson, J. F., Frank, D. W., Calvo, P. A., Bieler, B. M., Marks, M. S. A common temperature-sensitive allelic form of human tyrosinase is retained in the endoplasmic reticulum at the nonpermissive temperature. J. Biol. Chem. 275: 12281-12289, 2000. [PubMed: 10766867] [Full Text: https://doi.org/10.1074/jbc.275.16.12281]
Bishop, D. T., Demenais, F., Iles, M. M., Harland, M., Taylor, J. C., Corda, E., Randerson-Moor, J., Aitken, J. F., Avril, M.-F., Azizi, E., Bakker, B., Bianchi-Scarra, G., and 41 others. Genome-wide association study identifies three loci associated with melanoma risk. Nature Genet. 41: 920-925, 2009. [PubMed: 19578364] [Full Text: https://doi.org/10.1038/ng.411]
Chiang, P.-W., Drautz, J. M., Tsai, A. C.-H., Spector, E., Clericuzio, C. L. A new hypothesis of OCA1B. (Letter) Am. J. Med. Genet. 146A: 2968-2970, 2008. [PubMed: 18925668] [Full Text: https://doi.org/10.1002/ajmg.a.32539]
Chiang, P.-W., Spector, E., Tsai, A. C.-H. Oculocutaneous albinism spectrum. (Letter) Am. J. Med. Genet. 149A: 1590-1591, 2009. [PubMed: 19533789] [Full Text: https://doi.org/10.1002/ajmg.a.32939]
Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. A population-based study of autosomal-recessive disease-causing mutations in a founder population. Am. J. Hum. Genet. 91: 608-620, 2012. [PubMed: 22981120] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.007]
Fukai, K., Holmes, S. A., Lucchese, N. J., Siu, V. M., Weleber, R. G., Schnur, R. E., Spritz, R. A. Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism. Nature Genet. 9: 92-95, 1995. [PubMed: 7704033] [Full Text: https://doi.org/10.1038/ng0195-92]
Giebel, L. B., Musarella, M. A., Spritz, R. A. A nonsense mutation in the tyrosinase gene of Afghan patients with tyrosinase negative (type IA) oculocutaneous albinism. J. Med. Genet. 28: 464-467, 1991. [PubMed: 1832718] [Full Text: https://doi.org/10.1136/jmg.28.7.464]
Giebel, L. B., Spritz, R. A. RFLP for MboI in the human tyrosinase (TYR) gene detected by PCR. Nucleic Acids Res. 18: 3103, 1990. [PubMed: 1971925] [Full Text: https://doi.org/10.1093/nar/18.10.3103-a]
Giebel, L. B., Strunk, K. M., Jackson, C. E., Hanifin, J. M., King, R. A., Spritz, R. A. Tyrosinase gene mutations in patients with type IB ('yellow') oculocutaneous albinism. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A156, 1990.
Giebel, L. B., Strunk, K. M., Spritz, R. A. Organization and nucleotide sequences of the human tyrosinase gene and a truncated tyrosinase-related segment. Genomics 9: 435-445, 1991. [PubMed: 1903356] [Full Text: https://doi.org/10.1016/0888-7543(91)90409-8]
Gudbjartsson, D. F., Sulem, P., Stacey, S. N., Goldstein, A. M., Rafner, T., Sigurgeirsson, B., Benediktsdottir, K. R., Thorisdottir, K., Ragnarsson, R., Sveinsdottir, S. G., Magnusson, V., Lindblom, A., and 26 others. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nature Genet. 40: 886-891, 2008. Note: Erratum: Nature Genet. 40: 1029 only, 2008. [PubMed: 18488027] [Full Text: https://doi.org/10.1038/ng.161]
Hutton, S. M., Spritz, R. A. A comprehensive genetic study of autosomal recessive ocular albinism in Caucasian patients. Invest. Ophthal. Vis. Sci. 49: 868-872, 2008. [PubMed: 18326704] [Full Text: https://doi.org/10.1167/iovs.07-0791]
Jackson, I. J., Bennett, D. C. Identification of the albino mutation of mouse tyrosinase by analysis of an in vitro revertant. Proc. Nat. Acad. Sci. 87: 7010-7014, 1990. [PubMed: 2119500] [Full Text: https://doi.org/10.1073/pnas.87.18.7010]
Kikuchi, H., Hara, S., Ishiguro, S., Tamai, M., Watanabe, M. Detection of point mutation in the tyrosinase gene of a Japanese albino patient by a direct sequencing of amplified DNA. Hum. Genet. 85: 123-124, 1990. [PubMed: 2113511] [Full Text: https://doi.org/10.1007/BF00276337]
King, R. A., Mentink, M. M., Oetting, W. S. Non-random distribution of missense mutations within the human tyrosinase gene in type I (tyrosinase-related) oculocutaneous albinism. Molec. Biol. Med. 8: 19-29, 1991. [PubMed: 1943686]
King, R. A., Townsend, D., Oetting, W. S., Spritz, R. A. An unusual pigment pattern in type I oculocutaneous albinism (OCA) resulting from a temperature-sensitive enzyme. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A8, 1989.
King, R. A., Townsend, D., Oetting, W., Summers, C. G., Olds, D. P., White, J. G., Spritz, R. A. Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism. J. Clin. Invest. 87: 1046-1053, 1991. [PubMed: 1900307] [Full Text: https://doi.org/10.1172/JCI115064]
Kwon, B. S., Halaban, R., Chintamaneni, C. Molecular basis of mouse Himalayan mutation. Biochem. Biophys. Res. Commun. 161: 252-260, 1989. [PubMed: 2567165] [Full Text: https://doi.org/10.1016/0006-291x(89)91588-x]
Kwon, B. S., Haq, A. K., Pomerantz, S. H., Halaban, R. Isolation and sequence of a cDNA clone for human tyrosinase that maps at the mouse c-albino locus. Proc. Nat. Acad. Sci. 84: 7473-7477, 1987. Note: Erratum: Proc. Nat. Acad. Sci. 85: 6352 only, 1988. [PubMed: 2823263] [Full Text: https://doi.org/10.1073/pnas.84.21.7473]
Kwon, B. S., Haq, A. K., Wakulchik, M., Kestler, D., Barton, D. E., Francke, U., Lamoreux, M. L., Whitney, J. B., III, Halaban, R. Isolation, chromosomal mapping, and expression of the mouse tyrosinase gene. J. Invest. Derm. 93: 589-594, 1989. [PubMed: 2507645] [Full Text: https://doi.org/10.1111/1523-1747.ep12319693]
Kwon, B. S., Wakulchik, M., Haq, A. K., Halaban, R., Kestler, D. Sequence analysis of mouse tyrosinase cDNA and the effect of melanotropin on its gene expression. Biochem. Biophys. Res. Commun. 153: 1301-1309, 1988. [PubMed: 3134020] [Full Text: https://doi.org/10.1016/s0006-291x(88)81370-6]
Morell, R., Spritz, R. A., Ho, L., Pierpont, J., Guo, W., Friedman, T. B., Asher, J. H., Jr. Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA). Hum. Molec. Genet. 6: 659-664, 1997. [PubMed: 9158138] [Full Text: https://doi.org/10.1093/hmg/6.5.659]
Nance, W. E., Jackson, C. E., Witkop, C. J., Jr. Amish albinism: a distinctive autosomal recessive phenotype. Am. J. Hum. Genet. 22: 579-586, 1970. [PubMed: 5516239]
Oetting, W. S., King, R. A. Mutations within the promoter region of the tyrosinase gene in type I (tyrosinase-related) oculocutaneous albinism. (Abstract) Clin. Res. 39: 267A, 1991.
Oetting, W. S., King, R. A. Molecular analysis of type I-A (tyrosine negative) oculocutaneous albinism. Hum. Genet. 90: 258-262, 1992. [PubMed: 1487241] [Full Text: https://doi.org/10.1007/BF00220074]
Oetting, W. S., King, R. A. Molecular basis of type I (tryrosinase (sic)-related) oculocutaneous albinism: mutations and polymorphisms of the human tyrosinase gene. Hum. Mutat. 2: 1-6, 1993. [PubMed: 8477259] [Full Text: https://doi.org/10.1002/humu.1380020102]
Oetting, W. S., King, R. A. Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Hum. Mutat. 13: 99-115, 1999. [PubMed: 10094567] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:2<99::AID-HUMU2>3.0.CO;2-C]
Oetting, W. S., Mentink, M. M., Summers, C. G., Lewis, R. A., White, J. G., King, R. A. Three different frameshift mutations of the tyrosinase gene in type IA oculocutaneous albinism. Am. J. Hum. Genet. 49: 199-206, 1991. [PubMed: 1905879]
Oetting, W. S., Pietsch, J., Brott, M. J., Savage, S., Fryer, J. P., Summers, C. G., King, R. A. The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Am. J. Med. Genet. 149A: 466-469, 2009. [PubMed: 19208379] [Full Text: https://doi.org/10.1002/ajmg.a.32654]
Oetting, W. S., Witkop, C. J., Jr., Brown, S. A., Colomer, R., Fryer, J. P., Bloom, K. E., King, R. A. A frequent tyrosinase gene mutation associated with type I-A (tyrosinase-negative) oculocutaneous albinism in Puerto Rico. Am. J. Hum. Genet. 52: 17-23, 1993. [PubMed: 8434585]
Page-McCaw, P. S., Chung, S. C., Muto, A., Roeser, T., Staub, W., Finger-Baier, K. C., Korenbrot, J. I., Baier, H. Retinal network adaptation to bright light requires tyrosinase. Nature Neurosci. 7: 1329-1336, 2004. [PubMed: 15516923] [Full Text: https://doi.org/10.1038/nn1344]
Passmore, L. A., Kaesmann-Kellner, B., Weber, B. H. F. Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population. Hum. Genet. 105: 200-210, 1999. [PubMed: 10987646] [Full Text: https://doi.org/10.1007/s004390051090]
Petris, M. J., Strausak, D., Mercer, J. F. B. The Menkes copper transporter is required for the activation of tyrosinase. Hum. Molec. Genet. 9: 2845-2851, 2000. [PubMed: 11092760] [Full Text: https://doi.org/10.1093/hmg/9.19.2845]
Polanowski, A. M., Robinson-Laverick, S. M., Paton, D., Jarman, S. N. Variation in the tyrosinase gene associated with a white humpback whale (Megaptera novaeangliae). J. Hered. 103: 130-133, 2012. [PubMed: 22140253] [Full Text: https://doi.org/10.1093/jhered/esr108]
Ponnazhagan, S., Hou, L., Kwon, B. S. Structural organization of the human tyrosinase gene and sequence analysis and characterization of its promoter region. J. Invest. Derm. 102: 744-748, 1994. [PubMed: 8176257] [Full Text: https://doi.org/10.1111/1523-1747.ep12376924]
Schmidt-Kuntzel, A., Eizirik, E., O'Brien, S. J., Menotti-Raymond, M. Tyrosinase and tyrosinase related protein I alleles specify domestic cat coat color phenotypes of the albino and brown loci. J. Hered. 96: 289-301, 2005. [PubMed: 15858157] [Full Text: https://doi.org/10.1093/jhered/esi066]
Setty, S. R. G., Tenza, D., Sviderskaya, E. V., Bennett, D. C., Raposo, G., Marks, M. S. Cell-specific ATP7A transport sustains copper-deficient tyrosinase activity in melanosomes. Nature 454: 1142-1146, 2008. [PubMed: 18650808] [Full Text: https://doi.org/10.1038/nature07163]
Shibahara, S., Tomita, Y., Tagami, H., Muller, R. M., Cohen, T. Molecular basis for the heterogeneity of human tyrosinase. Tohoku J. Exp. Med. 156: 403-414, 1988. [PubMed: 2854305] [Full Text: https://doi.org/10.1620/tjem.156.403]
Simeonov, D. R., Wang, X., Wang, C., Sergeev, Y., Dolinska, M., Bower, M., Fischer, R., Winer, D., Dubrovsky, G., Balog, J. Z., Huizing, M., Hart, R., Zein, W. M., Gahl, W. A., Brooks, B. P., Adams, D. R. DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics. Hum. Mutat. 34: 827-835, 2013. [PubMed: 23504663] [Full Text: https://doi.org/10.1002/humu.22315]
Spritz, R. A., Giebel, L. B., Tripathi, R. K., Strunk, K. M. Structure and polymorphisms of the human tyrosinase gene and a truncated tyrosinase pseudogene. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A117, 1990.
Spritz, R. A., Strunk, K., King, R. A. Molecular analyses of the tyrosinase gene in patients with tyrosinase-deficient oculocutaneous albinism. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A221, 1989.
Spritz, R. A., Strunk, K. M., Hsieh, C.-L., Sekhon, G. S., Francke, U. Homozygous tyrosinase gene mutation in an American black with tyrosinase-negative (type IA) oculocutaneous albinism. Am. J. Hum. Genet. 48: 318-324, 1991. [PubMed: 1899321]
Spritz, R. A. Molecular genetics of oculocutaneous albinism. Hum. Molec. Genet. 3: 1469-1475, 1994. [PubMed: 7849740] [Full Text: https://doi.org/10.1093/hmg/3.suppl_1.1469]
Spritz, R., Strunk, K., Oetting, W., King, R. RFLP for TaqI at the human tyrosinase locus. Nucleic Acids Res. 16: 9890, 1988. [PubMed: 2903492] [Full Text: https://doi.org/10.1093/nar/16.20.9890]
Stokowski, R. P., Pant, P. V. K., Dadd, T., Fereday, A., Hinds, D. A., Jarman, C., Filsell, W., Ginger, R. S., Green, M. R., van der Ouderaa, F. J., Cox, D. R. A genomewide association study of skin pigmentation in a South Asian population. Am. J. Hum. Genet. 81: 1119-1132, 2007. [PubMed: 17999355] [Full Text: https://doi.org/10.1086/522235]
Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Jakobsdottir, M., Steinberg, S., Gudjonsson, S. A., Palsson, A., Thorleifsson, G., Palsson, S., Sigurgeirsson, B., and 13 others. Two newly identified genetic determinants of pigmentation in Europeans. Nature Genet. 40: 835-837, 2008. [PubMed: 18488028] [Full Text: https://doi.org/10.1038/ng.160]
Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genet. 39: 1443-1452, 2007. [PubMed: 17952075] [Full Text: https://doi.org/10.1038/ng.2007.13]
Takeda, A., Tomita, Y., Matsunaga, J., Tagami, H., Shibahara, S. Molecular basis of tyrosinase-negative oculocutaneous albinism: a single base mutation in the tyrosinase gene causing arginine to glutamine substitution at position 59. J. Biol. Chem. 265: 17792-17797, 1990. [PubMed: 2120217]
Tomita, Y., Takeda, A., Okinaga, S., Tagami, H., Shibahara, S. Human oculocutaneous albinism caused by single base insertion in the tyrosinase gene. Biochem. Biophys. Res. Commun. 164: 990-996, 1989. [PubMed: 2511845] [Full Text: https://doi.org/10.1016/0006-291x(89)91767-1]
Tripathi, R. K., Strunk, K. M., Giebel, L. B., Weleber, R. G., Spritz, R. A. Tyrosinase gene mutations in type I (tyrosinase-deficient) oculocutaneous albinism define two clusters of missense substitutions. Am. J. Med. Genet. 43: 865-871, 1992. [PubMed: 1642278] [Full Text: https://doi.org/10.1002/ajmg.1320430523]