A Dosage-Dependent Dominant-Negative Mechanism of SLC45A2(W74R) in Autosomal Dominant Oculocutaneous Albinism Revealed by Zebrafish Modeling.

Abstract

PURPOSE: To investigate the clinical characteristics of autosomal dominant oculocutaneous albinism (OCA) and functionally validate the heterozygous SLC45A2(W74R) variant using a zebrafish model. METHODS: Three members of a Korean family with OCA underwent comprehensive clinical examinations. Targeted panel and genome sequencing were performed on the proband, and Sanger sequencing was performed on all affected family members. To assess the pathogenicity of the genetic variant, a slc45a2 knockout (KO) zebrafish model was generated using CRISPR technology. RESULTS: All three affected patients exhibited hair and iris hypopigmentation, with variable foveal hypoplasia and nystagmus. A heterozygous c.220T>C:p.(W74R) variant in SLC45A2 was identified and was absent in gnomAD v4.1. Multiple in silico predictions supported its pathogenicity (AlphaMissense: 0.993, CADD: 29.6, REVEL: 0.951). Genome sequencing revealed no additional pathogenic or common hypomorphic variants in other known OCA-related genes. The slc45a2 KO zebrafish exhibited a typical albino phenotype, which was rescued by melanocyte-specific expression of normal SLC45A2 but not by the SLC45A2(W74R) variant. Furthermore, the SLC45A2(W74R) variant suppressed pigmentation in heterozygous KO, but not in wild-type zebrafish, indicating a dominant-negative effect in a dosage-dependent manner. CONCLUSIONS: This study demonstrated that a heterozygous c.220T>C:p.(W74R) variant in SLC45A2 causes variable expressivity of OCA in a dominant inherited manner, and this variant interferes with melanogenesis in zebrafish. TRANSLATIONAL RELEVANCE: This study expands the mode of inheritance in OCA and provides crucial functional validation that is important for genetic counseling.