TYR – Oculocutaneous Albinism Type 1B

TYR encodes tyrosinase, a copper-containing enzyme catalyzing the rate-limiting step in melanin biosynthesis. Autosomal recessive loss-of-function and hypomorphic variants in TYR result in oculocutaneous albinism type 1 (OCA1), which subdivides into OCA1A (complete lack of pigment) and OCA1B (residual pigment). OCA1B is characterized by mild hypopigmentation at birth and eventual development of yellow to light brown hair and lighter skin tone compared to unaffected relatives, with variable ocular involvement. Molecular confirmation of TYR variants is critical for accurate subtype classification.

Extensive genetic evidence supports a definitive TYR–OCA1B association. Over 60 unrelated probands from at least 20 families have been reported with biallelic TYR variants causing OCA1B. These include a Japanese compound heterozygote for a known null allele and a splice site variant causing a milder phenotype ([PMID:10559577]), Puerto Rican siblings compound heterozygous for four TYR variants including c.575C>A (p.Ser192Tyr) and c.140G>A (p.Gly47Asp) ([PMID:38994739]), and large cohorts of Chinese and European patients with novel missense, nonsense, splice, insertion/deletion, and frameshift alleles ([PMID:10671066]; [PMID:24721949]; [PMID:26165494]). Segregation in multiplex families (including two affected siblings) and carrier status in unaffected relatives confirm autosomal recessive inheritance.

The TYR variant spectrum in OCA1B encompasses primarily missense mutations (e.g., p.Ser192Tyr, p.Gly47Asp) that retain partial enzymatic activity, as well as loss-of-function alleles (nonsense, frameshift, critical splice site). Multi-ethnic founder and recurrent alleles have been described: c.575C>A (p.Ser192Tyr) is prevalent in Puerto Rican and other populations, while novel variants such as c.216delA (p.Val74AlafsTer*) and c.721G>A (p.Ala241Thr) have been identified in Chinese cohorts.

A representative mild allele, c.575C>A (p.Ser192Tyr), recurs in diverse populations and correlates with retained tyrosinase function and pigment deposition, consistent with OCA1B ([PMID:38994739]). Functional studies demonstrate that hypomorphic alleles exhibit substantial endoplasmic reticulum (ER) retention, reduced DOPA oxidase activity, and partial rescue at permissive temperatures or by co-expression with chaperones ([PMID:2120217]; [PMID:27537549]). These assays confirm that residual tyrosinase activity underlies the milder OCA1B phenotype.

The primary pathogenic mechanism is haploinsufficiency of tyrosinase activity leading to decreased melanin synthesis. ER retention and misfolding of mutant proteins are consistent across multiple variants, and rescue of activity by pharmacological chaperones has been demonstrated in cell and animal models. Concordant genotype-phenotype correlations across in vitro, in vivo, and clinical observations reinforce pathogenicity assignments.

Some common TYR polymorphisms, notably c.1205G>A (p.Arg402Gln), exhibit temperature sensitivity and partial processing defects in vitro but do not independently cause OCA1B when present without a second pathogenic allele ([PMID:19208379]). This highlights the need for functional validation of hypomorphic alleles, especially in complex or digenic presentations.

In summary, TYR mutations are definitively associated with OCA1B. Comprehensive genotyping and functional testing of TYR variants enable precise diagnosis, inform prognostic counseling, and guide potential future targeted therapies. Key Take-home: Molecular confirmation of TYR alleles is essential for distinguishing OCA1B from other albinism subtypes and optimizing clinical management.

References

• Dermatology (Basel, Switzerland) • 1999 • A splicing mutation of the tyrosinase gene causes yellow oculocutaneous albinism in a Japanese patient with a pigmented phenotype. PMID:10559577
• Molecular Genetics & Genomic Medicine • 2024 • After an initial Hermansky-Pudlak syndrome clinical diagnosis, molecular testing reveals variants for oculocutaneous albinism type 1B: A case report. PMID:38994739
• Human Mutation • 1998 • Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. PMID:10671066
• European Journal of Dermatology • 2014 • A comprehensive study of oculocutaneous albinism type 1 reveals three previously unidentified alleles on the TYR gene. PMID:24721949
• Journal of Genetics and Genomics • 2015 • Prenatal genotyping of four common oculocutaneous albinism genes in 51 Chinese families. PMID:26165494
• The Journal of Biological Chemistry • 1990 • Molecular basis of tyrosinase-negative oculocutaneous albinism. A single base mutation in the tyrosinase gene causing arginine to glutamine substitution at position 59. PMID:2120217
• The British Journal of Dermatology • 2016 • Functional assessment of tyrosinase variants identified in individuals with albinism is essential for unequivocal determination of genotype-to-phenotype correlation. PMID:27537549
• American Journal of Medical Genetics Part A • 2009 • The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. PMID:19208379

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