p.P1379S, a benign variant with reduced ATP7B protein level in Wilson Disease.

JIMD Reports
Fan YiSi Houn Hahn

Abstract

Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by inherited defects in the ATP7B 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...Continue Reading

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