TYR – Oculocutaneous Albinism Type 1

Tyrosinase (TYR) is a copper‐containing, membrane‐bound glycoenzyme that catalyzes the rate‐limiting steps of melanin biosynthesis in melanocytes and retinal pigment epithelium (PMID:17355913). Pathogenic biallelic variants in TYR cause oculocutaneous albinism type 1 (OCA1; MONDO:0018135), characterized by absent or reduced pigmentation of skin, hair and eyes and associated ocular defects.

OCA1 is inherited in an autosomal recessive mode. Large case series demonstrate TYR mutations in 37.3% (19/51) of unselected Chinese OCA patients (PMID:38145795), 41/71 Han patients in China (PMID:24721949), and 122/268 patients bearing the c.1205G>A promoter/ser192‐arg402 haplotype (PMID:30472657). Reported variant classes include missense (~71%), insertions/deletions (~18%), delins, splice‐site, and nonsense changes (PMID:38145795). Founder and recurrent alleles have been documented in Eastern Indian (c.832C>T) (PMID:32115698) and Taiwanese cohorts (c.232_233insGGG) (PMID:10571953).

Segregation studies in multiple unrelated families confirm co‐segregation of biallelic TYR variants with OCA1 phenotype. For example, a novel promoter variant c.-89T>G and coding change c.47C>A (p.Ser16Tyr) were shown in compound heterozygosity with clear linkage and predicted loss of TYR activity (PMID:35413289). The representative coding variant c.47C>A (p.Ser16Tyr) illustrates signal‐sequence disruption leading to endoplasmic reticulum (ER) retention.

Mechanistically, pathogenic TYR variants cause loss or reduction of enzymatic activity via protein misfolding and ER retention. Albino mouse and human mutant proteins such as R402Q and T373K exhibit temperature‐sensitive folding defects and fail to traffic to melanosomes (PMID:10766867, PMID:10823941). In vitro Endo H assays confirm prolonged association with ER chaperones and complete loss of glycan maturation in severe alleles.

Animal and cellular rescue experiments further support haploinsufficiency as the pathogenic mechanism. CRISPR/Cas9 correction of T373K in rabbit embryos restores melanin synthesis in hair follicles and irides (PMID:30274819), and hypomorphic in‐frame deletions in mouse Tyr yield graded coat‐color phenotypes (PMID:27224051). Biochemical characterization of recombinant intramelanosomal domains mimicking OCA1A/B variants correlates residual activity with clinical severity (PMID:27775880).

Integration of robust genetic, segregation, functional, and animal model data fully supports a definitive gene–disease relationship. TYR variants account for ~50% of OCA1 worldwide and functional assays enable reliable genotype–phenotype correlations. Key Take-home: TYR loss‐of‐function via ER retention underlies autosomal recessive OCA1, guiding molecular diagnosis, genetic counseling, and potential targeted therapies.

References

• Progress in retinal and eye research • 2007 • Tyrosinase and ocular diseases: some novel thoughts on the molecular basis of oculocutaneous albinism type 1. PMID:17355913
• Experimental Eye Research • 2024 • TYR mutation in a Chinese population with oculocutaneous albinism: Molecular characteristics and ophthalmic manifestations. PMID:38145795
• The British Journal of Ophthalmology • 2019 • Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene. PMID:30472657
• The Journal of Biological Chemistry • 2022 • Identification and characterization of two novel noncoding tyrosinase (TYR) gene variants leading to oculocutaneous albinism type 1. PMID:35413289
• 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
• The Journal of Biological Chemistry • 2000 • A common temperature-sensitive allelic form of human tyrosinase is retained in the endoplasmic reticulum at the nonpermissive temperature. PMID:10766867
• Pigment Cell & Melanoma Research • 2017 • Oculocutaneous albinism type 1: link between mutations, tyrosinase conformational stability, and enzymatic activity. PMID:27775880
• EBioMedicine • 2018 • Functional validation of the albinism-associated tyrosinase T373K SNP by CRISPR/Cas9-mediated homology-directed repair (HDR) in rabbits. PMID:30274819

Evidence Based Scoring (AI generated)