PUBLICATION
Common dominant-negative spectrum of SLC45A2 mutations in OCA4 defined by endoplasmic reticulum retention
- Authors
- Urushibata, H., Shimizu, N., Yatsuka, H., Soga, Y., Inoue, M., Oki, R., Kubota, T., Takeda, A., Hanada, R., Ihara, K., Hanada, T.
- ID
- ZDB-PUB-260309-5
- Date
- 2026
- Source
- Biochemical and Biophysical Research Communications 811: 153578 (Journal)
- Registered Authors
- Hanada, Reiko, Hanada, Toshikatsu
- Keywords
- Dominant-negative effect, Endoplasmic reticulum (ER), Oculocutaneous albinism type 4 (OCA4), SLC45A2, Zebrafish
- MeSH Terms
- none
- PubMed
- 41797184 Full text @ Biochem. Biophys. Res. Commun.
Citation
Urushibata, H., Shimizu, N., Yatsuka, H., Soga, Y., Inoue, M., Oki, R., Kubota, T., Takeda, A., Hanada, R., Ihara, K., Hanada, T. (2026) Common dominant-negative spectrum of SLC45A2 mutations in OCA4 defined by endoplasmic reticulum retention. Biochemical and Biophysical Research Communications. 811:153578.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping