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Oculocutaneous albinism type 2 (OCA2) is an autosomal recessive pigmentary disorder caused by biallelic variants in the OCA2 gene, encoding a melanosomal membrane protein critical for tyrosinase processing and melanin synthesis. Patients characteristically present with generalized hypopigmentation of skin, hair, and eyes, nystagmus, reduced visual acuity, and photophobia. The association between OCA2 (HGNC:8101) and OCA2 (MONDO:0008746) has been robustly validated through linkage, segregation, and functional studies over three decades, supporting a Definitive ClinGen classification.
Genetic evidence for OCA2 involvement includes identification of pathogenic variants in >288 probands from >200 unrelated families worldwide, consistent with autosomal recessive inheritance and cosegregation in multiplex pedigrees. A consanguineous Iranian family with a novel homozygous missense variant c.1274T>G (p.Met425Arg) confirmed by segregation analysis underscores the clinical relevance of missense alleles [PMID:40735666]. Linkage in 41 South African families established locus homogeneity at chromosome 15q11–q13 [PMID:8198130], and an intragenic deletion accounts for 78% of OCA2 alleles in southern African Negroids (114/146 chromosomes) with a shared founder haplotype [PMID:7887411]. In a Chinese cohort of 114 patients, targeted sequencing revealed 31 OCA2 variants, including splicing, frameshift, and novel missense alleles, expanding the mutation spectrum [PMID:31077556].
The variant spectrum in OCA2 encompasses missense (e.g., p.Met425Arg), nonsense (e.g., p.Trp204Ter), frameshift (e.g., p.Ile484ThrfsTer19), splice site (e.g., c.1951+1G>A), and copy‐number changes (exon 7 deletion), with recurrent founder alleles in African and Polish populations. Loss-of-function variants predominate, and hypomorphic alleles contribute to phenotypic variability. Recurrent intragenic deletions and deep-intronic splice defects illustrate the need for CNV and RNA analyses in genetic testing.
Functional studies demonstrate that OCA2 variants disrupt melanosome pH regulation and melanogenic enzyme trafficking. Minigene assays on exon 10 VUS show aberrant exon skipping in patient blood RNA, confirming splicing defects for both intronic and synonymous variants [PMID:37650133]. Computational modeling and molecular dynamics of non‐synonymous variants (e.g., Arg305Trp) predict destabilization of transmembrane domains and loss of protein stability [PMID:23824587]. Heterologous expression in HeLa lysosomes confirms OCA2’s role in organelle pH neutralization, concordant with human hypopigmentation.
No studies have refuted the OCA2–OCA2 association; all reported variants segregate with disease and functional assays are concordant with human phenotype. The comprehensive genetic and experimental data meet and exceed ClinGen criteria for a Definitive gene‐disease relationship.
Taken together, the integration of extensive genetic, segregation, and functional evidence establishes OCA2 as the causative gene for autosomal recessive oculocutaneous albinism type 2. Comprehensive molecular testing, including sequencing and CNV analysis, is recommended for accurate diagnosis, genetic counseling, and management.
Gene–Disease AssociationDefinitiveMultiple independent studies in diverse populations with linkage, segregation, and functional concordance over 30 years Genetic EvidenceStrongOver 288 probands from >200 families; variant spectrum includes null and missense alleles; autosomal recessive segregation Functional EvidenceModerateIn vitro minigene assays and mRNA analyses demonstrate splicing defects; computational and structural modelling confirm protein destabilization |