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Mechanism of the unstable proteins generated by P346H-BEST1 and P233-LBEST1mutations and their role in causing RP50 and BVMD

LU Qing-Xiang¹, YANG Jing-Ye¹, TIAN Hong-Xia¹, ZHOU Zhong-Xue¹, ZHOU Ding-An^2,*

¹School of Clinical Laboratory Science, Guizhou Medical University, Guiyang 550000, China；²Clinical Research Center, Guizhou Medical University, Guiyang 550000, China

Abstract

BEST1 mutations are associated with a spectrum of ocular disorders collectively termed Bestrophinopathies, including autosomal dominant Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), retinitis pigmentosa type 50 (RP50), and autosomal recessive bestrophinopathy (ARB). The molecular mechanisms underlying their distinct retinal phenotypes remain largely unknown. In this study, we characterized disease subtypes, causative genes, and mutation sites through comprehensive ophthalmic evaluations, whole-genome sequencing, and Sanger sequencing validation. Cellular immunofluorescence assays were performed to assess the impact of BEST1 mutations on the subcellular localization of Bestrophin-1. Protein stability of wild-type and mutant Bestrophin-1 was investigated in transiently transfected MDCK II cells treated with proteasome or lysosome inhibitors. We identified BEST1 c.1037C>A (p.P346H) and BEST1 c.698C>T (p.P233L) mutations in two families diagnosed with RP50 and BVMD, respectively. These mutations induced protein destabilization and subsequent degradation via the ubiquitin-proteasome-dependent pathway. Additionally, both p.P346H and p.P233L caused cytoplasmic mislocalization of the mutant Bestrophin-1 protein. Our findings suggest that the pathogenic mechanisms associated with p.P233L and p.P346H likely involve mislocalization of the mutant protein, protein instability and its targeted degradation via ubiquitinproteasome- dependent pathway.

Key words: Best vitelliform macular dystrophy (BVMD); retinitis pigmentosa 50 (RP50); protein degradation; cytoplasmic mislocalization

Received: 　　Accepted:

Corresponding author: 周定安　　E-mail:

DOI: 10.13294/j.aps.2026.0034

Citing This Article：

LU Qing-Xiang, YANG Jing-Ye, TIAN Hong-Xia, ZHOU Zhong-Xue, ZHOU Ding-An. Mechanism of the unstable proteins generated by P346H-BEST1 and P233-LBEST1mutations and their role in causing RP50 and BVMD. Acta Physiol Sin 2026; 78 (2): 443-451 (in Chinese with English abstract).