SLC45A2 – Oculocutaneous Albinism Type 4

Oculocutaneous albinism type 4 (OCA4) is an autosomal recessive hypopigmentation disorder caused by biallelic pathogenic variants in SLC45A2, characterized by reduced melanin synthesis in skin, hair, and eyes, often with iris transillumination and variable visual acuity deficits.

Genetic studies have identified approximately 48 unrelated probands with biallelic SLC45A2 variants across East Asian, European, and other populations (PMID:16162179). These include the founder p.Asp157Asn variant (c.469G>A (p.Asp157Asn)) in Japanese and Korean patients, compound heterozygous missense alleles c.301C>G (p.Arg101Gly) and c.1304C>A (p.Ser435Tyr) in a Chinese family (PMID:38337174), and multiple novel missense, nonsense, frameshift, and splice‐site changes in Japanese, Italian, and Dutch cohorts. Segregation of variants with disease in these consanguineous and outbred families is consistent with autosomal recessive inheritance.

The variant spectrum encompasses:

• Missense substitutions (e.g., c.301C>G (p.Arg101Gly); c.469G>A (p.Asp157Asn))
• Nonsense and frameshift mutations (e.g., c.152_153del (p.Val51fs))
• Canonical splice‐site alterations (e.g., c.1156+2dup)
• A promoter deletion (c.-492_489delAATG)

Functional assays corroborate pathogenicity: the p.Asp93Asn variant (c.277G>A) abolishes transport activity in Xenopus oocytes (PMID:25760657); p.Leu374Phe (c.1122G>T) reduces sucrose transport by ~90% (PMID:23071798); and p.His38Arg demonstrates loss of melanin synthesis in melanocyte cultures (PMID:19610114).

Cellular localization and biophysical studies reveal that SLC45A2 resides on mature melanosomes, where it contributes to pH neutralization essential for tyrosinase activity. Loss‐of‐function and unstable protein turnover (e.g., F374 variant) disrupt melanosome acidification and melanin production (PMID:32966160).

No studies have disputed this association, and the concordant genetic and experimental data meet ClinGen criteria for a Definitive gene–disease relationship.

Key Take-home: SLC45A2 loss‐of‐function variants cause OCA4 via disruption of melanosomal pH regulation and melanin synthesis; molecular diagnosis enables precise genetic counseling and clinical management.

References

• Pigment cell research • 2005 • OCA4: evidence for a founder effect for the p.D157N mutation of the MATP gene in Japanese and Korean. PMID:16162179
• Molecular genetics & genomic medicine • 2024 • Oculocutaneous albinism type 4: Novel compound heterozygous mutations in the SLC45A2 gene in a Chinese case. PMID:38337174
• PloS one • 2012 • Functional assessment of human coding mutations affecting skin pigmentation using zebrafish. PMID:23071798
• American journal of medical genetics. Part A • 2009 • Oculocutaneous albinism type IV: A boy of Moroccan descent with a novel mutation in SLC45A2. PMID:19610114
• Molecular biology of the cell • 2020 • SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation. PMID:32966160
• Molecular medicine reports • 2015 • Investigating polymorphisms in membrane-associated transporter protein SLC45A2, using sucrose transporters as a model. PMID:25760657

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