TYR – Oculocutaneous Albinism Type 1A

Tyrosinase (TYR) is the rate-limiting enzyme in melanin biosynthesis, and biallelic pathogenic variants in TYR cause tyrosinase-negative oculocutaneous albinism type 1A (OCA1A). Clinically, OCA1A presents with complete absence of melanin in skin, hair and eyes, severe visual impairment and nystagmus. The disorder follows an autosomal recessive inheritance pattern with unaffected carrier parents and homozygous or compound heterozygous affected offspring.

Genetic evidence includes over 50 unrelated probands with biallelic TYR variants in OCA1A families ([PMID:2120217], [PMID:1409445], [PMID:1711223]). The variant spectrum comprises more than 20 missense substitutions, including c.230G>A (p.Arg77Gln), >10 nonsense and frameshift alleles (e.g., c.1467dup (p.Ala490fs)), and multiple splice-site mutations. Population-specific alleles have been described in Japanese, Korean and Chinese cohorts, and founder variants account for up to 25 % of alleles in some ethnic groups.

Segregation analysis in multiple families confirms autosomal recessive transmission, with parents and siblings as heterozygous carriers and no affected carriers among >30 tested relatives ([PMID:8027570]). DNA-based prenatal diagnosis and carrier detection have been performed reliably by PCR and allele-specific assays in at least 10 families, demonstrating perfect co-segregation of disease alleles with the OCA1A phenotype.

Functional studies are concordant: transient expression of mutant TYR alleles fails to produce detectable enzyme activity in cell assays ([PMID:2120217]), and endoglycosidase H assays reveal ER retention of albino variants including p.Thr373Lys and p.Arg402Gln ([PMID:10823941]). CRISPR/Cas9-edited rabbit models bearing the p.Thr373Lys variant recapitulate hypopigmentation and demonstrate rescue of melanin production in knock-in animals ([PMID:30274819]).

One common variant, p.Arg402Gln (c.1205G>A), exhibits temperature-sensitive residual activity but does not cause OCA1A when present in trans with known pathogenic mutations, and is classified as a benign polymorphism ([PMID:19208379]).

Integration of extensive genetic and experimental data over >30 years supports a Definitive gene–disease association. TYR mutation analysis is essential for confirming OCA1A, guiding genetic counseling, carrier screening, and prenatal diagnosis. Key Take-home: Biallelic loss-of-function TYR variants cause OCA1A with complete penetrance and are diagnosable by molecular testing.

References

• 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
• Pigment cell research • 1992 • Molecular bases of tyrosinase-negative oculocutaneous albinism: a single base insertion or a missense point mutation in the tyrosinase gene. PMID:1409445
• Proceedings of the National Academy of Sciences of the United States of America • 1991 • A single base insertion in the putative transmembrane domain of the tyrosinase gene as a cause for tyrosinase-negative oculocutaneous albinism. PMID:1711223
• The Journal of investigative dermatology • 1994 • Prenatal diagnosis of oculocutaneous albinism by analysis of the fetal tyrosinase gene. PMID:8027570
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • Endoplasmic reticulum retention is a common defect associated with tyrosinase-negative albinism. PMID:10823941
• EBioMedicine • 2018 • Functional validation of the albinism-associated tyrosinase T373K SNP by CRISPR/Cas9-mediated homology-directed repair (HDR) in rabbits. PMID:30274819
• 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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