Yi Fan, Poskanzer Sheri A, Myers Candace T, Thies Jenny, Collins Christopher J, Dayuha Remwilyn, Duong Phi, Houwen Roderick, Hahn Si Houn
Seattle Children's Research Institute Seattle Washington USA.
Department of Pediatrics University of Washington, School of Medicine Seattle Washington USA.
JIMD Rep. 2020 May 19;54(1):32-36. doi: 10.1002/jmd2.12127. eCollection 2020 Jul.
Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by inherited defects in the gene 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.
ATP7B 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.
These 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.
威尔逊病（WD）是一种常染色体隐性铜转运障碍疾病，由该基因的遗传缺陷引起，导致铜在各器官中蓄积产生毒性。我们之前报道过一个三代连续受WD影响的家族，该家族携带p.P1379S变异，当时被分类为可能致病。然而，最近对p.P1379S变异的研究表明，其致病性的解读可能存在冲突。这促使我们利用一种替代肽来探索干血斑（DBS）中ATP7B的定量，以研究p.P1379S变异对两个携带常见p.P1379S变异的无关家族中ATP7B浓度的影响。
采用肽免疫亲和富集结合选择反应监测质谱法（免疫-SRM）对ATP7B进行定量，该方法利用抗体介导从DBS中捕获肽。两名WD患者的ATP7B水平检测不到，而四名携带一个已知致病变异和p.P1379S的复合杂合子儿童的ATP7B水平显著降低。值得注意的是，尽管这四名儿童未接受WD治疗，但均无症状，实验室检查结果也无异常。
这两个家族表明，p.P1379S与两个已知致病变异复合时，会导致蛋白质水平显著降低，但仍保留足够功能以维持正常铜稳态。这意味着p.P1379S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指导患者护理并避免不必要的治疗。
