Common dominant-negative spectrum of SLC45A2 mutations in OCA4 defined by endoplasmic reticulum retention

Oculocutaneous albinism type 4 (OCA4) is traditionally classified as an autosomal recessive disorder. Although the human Y70H variant has recently been suggested to exert a dominant-negative effect, it remains unknown whether this represents an isolated rarity or a manifestation of a broader pathogenic principle. Here, we identified a common dominant-negative SLC45A2 mutation spectrum based on its intracellular localization. Using a zebrafish model to systematically screen ten clinical variants, we identified four specific mutations, Y70H, D157 N, G188V, and L374F, which exerted potent dominant-negative effects in vivo. Subcellular localization analysis in B16 melanoma cells revealed that these mutant proteins exhibited significantly higher endoplasmic reticulum (ER) occupancy than the wild-type (WT) protein. Importantly, these variants act as "molecular traps" by physically sequestering WT SLC45A2 within the ER, thereby drastically reducing its delivery to TYRP1-positive melanosomes. Our findings demonstrate that dominant inheritance in OCA4 is driven by the spatial sequestration of functional proteins within the ER quality control machinery. This study establishes a new conceptual framework for the molecular diagnosis of OCA4 and provides a functional rationale for the use of pharmacological chaperones to rescue trapped transporters in membrane protein disorders.