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P346H-BEST1和P233L-BEST1突变产生不稳定蛋白引起视网膜色素变性50型(RP50)和Best黄斑营养不良症(BVMD)的机制

卢清香¹, 杨敬业¹, 田洪霞¹, 周忠雪¹, 周定安^2,*

¹贵州医科大学医学检验学院，贵阳 550000；²贵州医科大学临床医学研究中心，贵阳 550000

摘要

BEST1突变与广泛的眼部疾病有关，统称为Best病(Bestrophinopathies)，包括常染色体显性遗传的Best黄斑营养不良症(Best vitelliform macular dystrophy, BVMD)、成人发病黄斑营养不良症(adult-onset vitelliform macular dystrophy, AVMD)、玻璃体视网膜脉络膜病(autosomal dominant vitreoretinochoroidopathy, ADVIRC)、视网膜色素变性50 型(retinitis pigmentosa50, RP50)和常染色体隐性黄斑营养不良症(autosomal recessive bestrophinopathy, ARB)等。Best 病独特的视网膜表型背后的分子机制大多是未知的。本研究通过详细的眼科检查、基因组测序和Sanger 测序确定疾病类型、致病基因及突变位点。细胞免疫荧光测定BEST1 突变对Bestrophin-1 蛋白细胞定位的影响。在瞬时转染的MDCK II 细胞中加入蛋白酶体或溶酶体抑制剂，研究野生型和突变型Bestrophin-1 蛋白的稳定性。本研究鉴定了诊断为RP50 和BVMD两个家系中BEST1 c.1037C>A，p.(P346H)和BEST1 c.698C>T，p.(P233L)突变，这两个位点突变可能导致蛋白质不稳定，并通过泛素-蛋白酶体依赖途径降解。另外，BEST1 c.1037C>A，p.(P346H)和BEST1 c.698C>T，p.(P233L)突变使Bestrophin-1 突变蛋白在细胞内错误定位。以上结果提示与p.P233L 和p.P346H相关的致病机制可能涉及突变蛋白错误定位、蛋白不稳定和被泛素-蛋白酶体依赖机制降解。

关键词： Best黄斑营养不良症(BVMD); 视网膜色素变性50型(RP50); 蛋白降解; 胞质错定位

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

收稿日期：　　录用日期：

通讯作者：周定安　　E-mail:

DOI: 10.13294/j.aps.2026.0034

引用本文：

卢清香, 杨敬业, 田洪霞, 周忠雪, 周定安. P346H-BEST1和P233L-BEST1突变产生不稳定蛋白引起视网膜色素变性50型(RP50)和Best黄斑营养不良症(BVMD)的机制[J]. 生理学报 2026; 78 (2): 443-451.

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).