| *115501 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYROSINASE-RELATED PROTEIN 1; TYRP1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYRP; TRP CATALASE B; CATB; CAS2 GLYCOPROTEIN 75; GP75 b-PROTEIN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: TYRP1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 9p23 Genomic coordinates (GRCh37): 9:12,693,385 - 12,710,265 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Cloning | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cohen et al. (1990) reported the nucleotide and deduced amino acid sequence of the cDNA coding for the human homolog of the mouse b locus gene product. They referred to the protein as tyrosinase (606933)-related protein (TRP). Human TRP is shorter than the mouse Trp1 by 10 amino acids at the carboxy terminus, and the degree of sequence homology is about 93%. Box et al. (1998) determined the complete 24,667-bp sequence of the TYRP1 gene from 2 overlapping lambda clones. A LINE-1 repeat element was found immediately adjacent to and may demarcate the immediate 5-prime promoter region of the gene. Analysis of the TYRP1 gene in 100 Caucasians of varying hair color revealed no amino acid sequence variation, and no hemizygous mutant allele was found in connection with the hypopigmented phenotype of 2 patients with the 9p- syndrome (158170). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Halaban and Moellmann (1990) showed that the b locus protein is a catalase and is identical to a known human melanosomal protein, gp75. They referred to the protein as catalase B. The b mutation is in a heme-associated domain. The B(lt) mutation renders the protein susceptible to rapid proteolytic degradation. During melanin synthesis, hydroperoxides are produced during autooxidation of melanin precursor indoles by oxygen, and addition of catalase to tyrosinase reaction mixtures in vitro increases the yield of melanin. Absence of catalase B in b mutant melanocytes and concomitant brown instead of black coat color are indirect evidence that melanogenesis is regulated through peroxide levels in melanosomes, the subcellular organelles to which the 2 proteins, tyrosinase and catalase B, have been localized by ultrastructural immunocytochemistry. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Shibahara et al. (1992) demonstrated that the b gene in the mouse is about 18 kb long and organized into 8 exons and 7 introns. Sturm et al. (1995) showed that the TYRP1 protein is encoded in 7 exons spread over 24 kb of genomic DNA. By contrast, the TYRP2 (191275) protein is encoded by 8 exons. TYRP1, TYRP2, and the tyrosinase gene share a common C-terminal membrane spanning exon. The position of intron junctions suggested that TYRP1 was derived from a TYR duplication and then was itself duplicated to give rise to the TYRP2 gene. The comparisons also suggested that at least some of the introns within the TYR, TYRP1, and TYRP2 coding regions were gained after duplication and that intron slippage was unlikely to have occurred. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ramsay et al. (1991) referred to the human gene as CAS2 since its product is thought to have catalase activity. By Southern blot analysis with 2 somatic cell hybrid lines, one with chromosome 9 as its only human component and another with 9q as its only human component, Ramsay et al. (1991) and Chintamaneni et al. (1991) demonstrated that CAS2 maps to 9p. This was confirmed by in situ hybridization, which demonstrated location of the gene in the region 9pter-p22. They were prompted to seek mapping on chromosome 9 because of the considerable homology between human chromosome 9 and mouse chromosome 4. By species-specific PCR in connection with human/rodent somatic cell hybrids, Abbott et al. (1991) also mapped the TYRP gene to human 9p. Murty et al. (1992) refined the assignment to 9p23. They pointed out that the 9p region has been reported to be altered nonrandomly in human melanoma, suggesting a role for the region near the TYRP locus in melanocyte transformation. However, the work of Fountain et al. (1992) excluded the TYRP locus from involvement in cutaneous malignant melanoma (155600). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Oculocutaneous Albinism-3 In an African American male with oculocutaneous albinism (OCA3; 203290) whose cultured melanocytes showed an absence of immune-reactive TYRP1 and in whom analysis of mRNA revealed that transcription of TYRP1 was completely absent, Boissy et al. (1996) identified homozygosity for a 1-bp deletion in the TYRP1 gene (368delA; 115501.0001), resulting in premature truncation at codon 384. His fraternal twin was not affected. Boissy et al. (1996) proposed that the association of this mutation with absence of a transcript is due to decreased stability of the truncated transcript, and that a reduction in tyrosine hydroxylase activity in melanocytes from the affected twin is due to the regulatory role of TYRP1 on tyrosine hydroxylase activity of tyrosinase. Manga et al. (1997) analyzed the TYRP1 gene in 19 unrelated southern African blacks with so-called 'rufous OCA (ROCA)' and identified compound heterozygosity for 368delA and a nonsense mutation (S166X; 115501.0002) in 17 of the 19 patients; the remaining 2 patients carried the 1-bp deletion but no mutations were identified in the other allele. Manga et al. (1997) suggested that ROCA caused by mutations in the TYRP1 gene should be designated OCA3. In a consanguineous Pakistani family with OCA, Forshew et al. (2005) identified homozygosity for a nonsense mutation in the TYRP1 gene (115501.0003). The authors stated that this was the first TYRP1 mutation in non-Africans. In a Caucasian German boy with OCA, who was negative for mutations in the TYR (606933) and OCA2 genes, Rooryck et al. (2006) identified compound heterozygosity for a missense mutation (R356E; 115501.0004) and a 1-bp deletion (106delT; 115501.0005) in the TYRP1 gene. In a boy of Asian Indian origin with reddish hair, brown irides, nystagmus, and lightly pigmented skin, who was negative for mutations in the TYR, OCA2, and SLC45A2 (606202) genes, Chiang et al. (2009) identified homozygosity for a 4-bp deletion in the TYRP1 gene (115501.0006). The unaffected parents were both heterozygous for the deletion. Skin/Hair/Eye Pigmentation, Variation in, 11 For discussion of an association between variation in the TYRP1 gene and variation in skin, hair, and/or eye pigmentation, see SHEP11 (612271). Melanesian Blond Hair In individuals from the Solomon Islands with blond hair (see 612271), Kenny et al. (2012) identified homozygosity for an arg-to-cys substitution at codon 93 of the TYRP1 gene (R93C; 115501.0007). Kenny et al. (2012) noted similarity between the R93C mutation in humans and the mutation underlying the brown(light) phenotype of the mouse, R38C. The brown(light) mouse exhibits reduced Tyrp1 stability and catalytic function, resulting in decreased melanin content in hair, and Kenny et al. (2012) considered it likely that the human R93C mutation operates via a similar mechanism. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Shibahara et al. (1992) found 2 missense mutations, a cys-to-tyr substitution at position 86 (codon 110) and an arg-to-cys substitution at position 302 (codon 326), in 2 b-mutant mouse strains. Johnson and Jackson (1992) characterized 'light,' a dominant mutant allele at the mouse 'brown' locus. The mutation results in hairs pigmented only at their tips. They showed that the phenotype is due to premature melanocyte death and, by sequencing the tyrosinase-related protein-1 cDNA from light mice, demonstrated a single base alteration causing an arg-to-cys change in the protein. Premature melanocyte death occurred only in pigmented mice, indicating that the cell death is mediated through the inherent cytotoxicity of pigment production. They suggested that this gene should be studied as a candidate gene in premature graying in humans (139100). The brown(light) phenotype is caused by an arg38-to-cys substitution (R38C) that is thought to interfere with disulfide bridges formed by the 15-cys EGF repeat near the N terminus of the Tyrp1 protein (summary by Kenny et al., 2012). Schmidt-Kuntzel et al. (2005) found that sequence variants in the Tyrp1 gene caused the 'chocolate' and 'cinnamon' alleles of the brown locus in domestic cats. A second tyrosinase-related protein exists (TYRP2; 191275), the mouse homolog of which is encoded on chromosome 14 and is the site of the 'slaty' mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| History | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kwon et al. (1989) isolated 2 melanocyte-specific cDNAs and ascribed both to tyrosinase (606933). Based on deduced amino acid sequence, both code for glycoproteins of similar size, with a membrane-spanning domain and conserved positions of cysteine and histidine. One clone was assigned to the brown (b) locus on mouse chromosome 4 (Jackson, 1988); the other, to the c locus on mouse chromosome 7 and to human chromosome 11 (tyrosinase). The mutant b allele confers brown coat color, and the B(lt) allele confers an almost white color to normally black mice. Transfected wildtype c locus cDNA induced tyrosinase activity and melanin synthesis in fibroblasts, amelanotic melanoma cells, albino melanocytes, and albino transgenic mice, whereas wildtype b locus cDNA did not. Evidence suggested that the 'brown albinism' mutation (203200) was homologous to 'brown' in the mouse (King, 1992). Brown oculocutaneous albinism in humans results from mutation in the OCA2 gene (611409). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYRP1, 1-BP DEL, 368A | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In an African American fraternal twin with type III oculocutaneous albinism (OCA3; 203290), Boissy et al. (1996) found a single basepair deletion (A) in exon 6. The deletion of the A in codon 368 led to a premature stop at codon 384. Manga et al. (1997) analyzed the TYRP1 gene in 19 unrelated southern African blacks with so-called 'rufous' OCA (ROCA) and identified compound heterozygosity for 368delA and a ser166-to-ter nonsense mutation (S166X; 115501.0002) in 17 of the 19 patients; the remaining 2 patients carried the 1-bp deletion but no mutations were identified in the other allele. In 1 family, 2 sibs with a phenotypically unclassified form of albinism who were compound heterozygotes for 368delA and S166X in TYRP1 were also found to be heterozygous for the common 2.7-kb mutation at the P locus (OCA2; 611409.0001). Manga et al. (1997) suggested that ROCA caused by mutations in the TYRP1 gene should be designated OCA3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALBINISM, OCULOCUTANEOUS, TYPE II, MODIFIER OF, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYRP1, SER166TER [dbSNP:rs104894130] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 115501.0001 and Manga et al. (1997). Chiang et al. (2008) reported a Hispanic girl with oculocutaneous albinism type II (OCA2; 203200) caused by compound heterozygous mutations in the OCA2 gene (611409). She had pale skin, blue irides, and visual defects, including horizontal nystagmus, irides that transilluminated light, absence of foveal reflexes, albinotic fundi, and decreased visual acuity. However, she also had curly reddish-blonde hair, which was unusual for the OCA2 phenotype. The unaffected mother was of Puerto Rican and Cuban descent, and the unaffected father was of Dominican and Ecuadorian descent. Each parent was heterozygous for an OCA2 mutation. Further genetic analysis identified heterozygosity for the S166X mutation in the TYRP1 gene in the girl and her father. The father, who had haploinsufficiency at the OCA2 and TYRP1 loci together, did not have a noticeable phenotype. Chiang et al. (2008) concluded that haploinsufficiency of TYRP1 can modify the OCA2 phenotype, resulting in red hair. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYRP1, ARG373TER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a consanguineous Pakistani family with oculocutaneous albinism (203290), Forshew et al. (2005) identified homozygosity for a 1117C-T transition in exon 6 of the TYRP1 gene, resulting in an arg373-to-ter (R373X) substitution. The authors stated that this was the first TYRP1 mutation reported in non-Africans. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYRP1, ARG356GLU | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Caucasian German boy with oculocutaneous albinism (OCA3; 203290), Rooryck et al. (2006) identified compound heterozygosity for a 1066G-A transition in exon 5 of the TYRP1 gene, resulting in an arg356-to-glu (R356E) substitution, and a de novo 1-bp deletion (106delT; 115501.0005) in exon 2, resulting in an immediate termination sequence at codon 36. The patient had yellow-gold hair with orange highlights, fair eyelashes, blue-green eyes with defects of the iris and nystagmus, several pigmented nevi, and pale yellow skin that did not tan but burned easily. The patient's unaffected mother and sister were heterozygous for the missense mutation, which was not found in 100 unrelated controls; the 1-bp deletion was not found in either parent or the sister. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYRP1, 1-BP DEL, 106T | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 115501.0004 and Rooryck et al. (2006). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYRP1, 4-BP DEL, 1057AACA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a boy of Asian Indian origin with oculocutaneous albinism (OCA3; 203290), who had reddish hair color, brown irides, nystagmus, and lightly pigmented skin, Chiang et al. (2009) identified homozygosity for a 4-bp deletion (1057delAACA) in exon 5 of the TYRP1 gene. The unaffected parents were both heterozygous for the deletion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TYRP1, ARG93CYS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In individuals from the Solomon Islands with blond hair (612271), Kenny et al. (2012) identified homozygosity for a C-to-T transition at chr9:12,694,273 (GRCh37) that corresponds to a predicted arg-to-cys mutation (R93C) in exon 2 of the TYRP1 gene at amino acid position 93 (R93C). The genotype was TT in blond- and CT or CC in dark-haired individuals. This mutation was present with an allele frequency of 0.26 on the Solomon Islands and was absent from 941 individuals from 52 worldwide populations. No evidence of European admixture was detected in this population. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muller et al. (1988) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TYRP1
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