p.P1379S, a benign variant with reduced ATP7B protein level in Wilson Disease.
p.P1379S, a benign variant with reduced ATP7B protein level in Wilson Disease.
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p.P1379S，威尔逊病中 ATP7B 蛋白水平降低的良性变异。
DOI：
10.1002/jmd2.12127
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hahn,SiHoun
中科院分区：
文献类型：
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作者：
Yi,Fan;Poskanzer,SheriA;Myers,CandaceT;Thies,Jenny;Collins,ChristopherJ;Dayuha,Remwilyn;Duong,Phi;Houwen,Roderick;Hahn,SiHoun
背景：肝豆状核变性(WD)是一种常染色体隐性铜转运障碍，由ATP7B基因的遗传缺陷引起，可导致铜在多个器官中的毒性蓄积。我们之前报告了一个连续三代受WD影响的家庭，该家庭携带变异体p.P1379S，当时被归类为可能致病。然而，最近对p.P1379S变异体的研究表明，对其致病性的解释可能存在冲突。为了研究p.P1379S变异对两个具有共同p.P1379S变异的无关家系ATP7B浓度的影响，我们探索了使用替代肽来定量干血斑点(DBS)中ATP7B的方法。方法和结果采用免疫亲和富集法和选择性反应监测质谱仪(IRC-SRM)相结合的方法对ATP7B进行定量，该方法利用抗体介导的DBS多肽捕获。两名WD患者的ATP7B水平未被检测到，而4名具有一个已知致病变异体和p.P1379S的复合杂合子儿童的ATP7B水平显著降低。值得注意的是，所有四名儿童都没有症状，没有异常的实验室后果，尽管没有接受WD治疗。结论这两个家庭证明，当p.P1379S与两个已知的致病变异体复合时，导致蛋白质水平显著降低，但保留了足够的功能，以维持正常的铜稳态。这意味着P.P1379S在本质上是良性的。更好地了解WD变异的性质和后果将有助于告知患者护理和避免不必要的治疗。
BackgroundWilson disease (WD) is an autosomal recessive disorder of copper transport caused by inherited defects in theATP7Bgene and results in toxic accumulation of copper in various organs. We previously reported a family with three consecutive generations affected by WD that carries the variant, p.P1379S, which was classified at the time as likely pathogenic. However, recent investigations of the p.P1379S variant indicate a possible conflict of interpretations regarding its pathogenicity. This led us to explore the quantification of ATP7B in dried blood spots (DBS) using a surrogate peptide to study the effects of the p.P1379S variant on ATP7B concentrations in two unrelated families with the common p.P1379S variant.Methods and resultsATP7B was quantified using the peptide immunoaffinity enrichment coupled with selected reaction monitoring mass spectrometry (immuno‐SRM) method which utilizes antibody‐mediated peptide capture from DBS. Two patients affected with WD had undetectable ATP7B level while four compound heterozygous children with one known pathogenic variant and the p.P1379S had significantly reduced ATP7B levels. Of note, all four children remain asymptomatic without abnormal laboratory consequences despite being untreated for WD.ConclusionThese two families demonstrated that p.P1379S, when compounded with two known pathogenic variants, resulted in significantly reduced protein levels but retained enough function to maintain normal copper homeostasis. This implies that p.P1379S is benign in nature. A better understanding of the nature and consequences of variants in WD will help in informing patient care and avoiding unnecessary treatments.