Identification of potential modifier genes in Chinese patients with Wilson disease

Abstract

Themutations in modifier genesmay contribute to some inherited diseases includingWilson disease (WD).This studywas designed to identify potentialmodifier genes that contribute toWD.A total of 10WDpatientswith single or no heterozygous ATP7Bmutationswere recruited for whole-exome sequencing (WES). Five hundred and thirteen candidate genes, of which the genetic variants present in at least two patients,were identified. In order to clarifywhich proteins might be involved in copper transfer ormetabolism processes, the isobaric tags for relative and absolute quantitation (iTRAQ) was performed to identify the differentially expressed proteins between normal and CuSO4-treated cell lines. Thirteen genes/proteins were identified by both WES and iTRAQ, indicating that disease-causing variants of these genesmay actually contribute to the aberrant copper ion accumulation. Additionally, the c.86C > T (p.S29L)mutation in the SLC31A2 gene (coding CTR2) has a relative higher frequency in our cohort of WD patients (6/191) than reported (0.0024 in gnomAD database) in our healthy donors (0/109), and CTR2S29L leads to increased intracellular Cu concentration and Cu-induced apoptosis in cultured cell lines. In conclusion, theWES and iTRAQ approaches successfully identified several disease-causing variants in potential modifier genes that may be involved in the WD phenotype.