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首页> 美国卫生研究院文献>Human Molecular Genetics >BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes
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BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes

机译：BEST1蛋白的稳定性和降解途径在常染色体显性Best病和常染色体隐性Bestrophinosis之间存在差异这说明了不同的视网膜表型

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摘要

Mutations in bestrophin-1 (BEST1) are associated with distinct retinopathies, notably three forms with autosomal dominant inheritance and one condition with an autosomal recessive mode of transmission. The molecular mechanisms underlying their distinct retinal phenotypes are mostly unknown. Although heterozygous missense mutations in BEST1 reveal dominant-negative effects in patients with autosomal dominant Best disease (BD), heterozygous mutations associated with autosomal recessive bestrophinopathy (ARB) display no disease phenotype. Here we show that the recessive mutations trigger a strong and fast protein degradation process in the endoplasmic reticulum (ER), thereby favoring a decreased stoichiometry of mutant versus normal BEST1 subunits in the assembly of the homo-pentameric BEST1 chloride channel. In contrast, dominant mutations escape ER-associated degradation and are subjected to a slightly delayed post-ER degradation via the endo-lysosomal degradation pathway. As a result, increased formation of a non-functional BEST1 channel occurs due to a roughly equimolar incorporation of normal and mutant BEST1 subunits into the channel complex. Taken together, our data provide insight into the molecular pathways of dominantly and recessively acting BEST1 missense mutations suggesting that the site of subcellular protein quality control as well as the rate and degree of mutant protein degradation are ultimately responsible for the distinct retinal disease phenotypes in BD and ARB.
机译：Bestrophin-1（BEST1）中的突变与独特的视网膜病变相关，特别是三种具有常染色体显性遗传的形式和一种具有常染色体隐性传播方式的疾病。其独特的视网膜表型的分子机制大多是未知的。尽管BEST1中的杂合错义突变在常染色体显性遗传性最佳疾病（BD）患者中显示出显性负性作用，但与常染色体隐性性甲虫病（ARB）相关的杂合突变未显示任何疾病表型。在这里，我们显示隐性突变触发内质网（ER）中的强大而快速的蛋白质降解过程，从而有利于同五聚体BEST1氯化物通道组装中突变体与正常BEST1亚基的化学计量降低。相反，显性突变逃脱了与ER相关的降解，并通过内溶酶体降解途径而经历了稍微延迟的ER后降解。结果，由于正常的和突变的BEST1亚基大致等摩尔地掺入通道复合物中，导致无功能的BEST1通道的形成增加。综上所述，我们的数据提供了对显性和隐性作用的BEST1错义突变的分子途径的深入了解，表明亚细胞蛋白质量控制的位点以及突变蛋白降解的速率和程度最终决定了BD中独特的视网膜疾病表型。和ARB。

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