Spectrum of ATP7B mutations and genotype–phenotype correlation in large‐scale Chinese patients with Wilson Disease

Abstract

Wilson disease (WD), an inherited disorder associated with ATP7B gene, has a wide spectrum of genotypes and phenotypes. In this study, we developed a rapid multiplex PCR-MassArray method for detecting 110 mutant alleles of interest, and used it to examine genomic DNA from 1222 patients and 110 healthy controls. In patients not found to have any mutation in the 110 selected alleles, PCR-Sanger sequencing was used to examine the ATP7B gene. We identified 88 mutations, including 9 novel mutations. Our analyses revealed p.Arg778Leu, p.Arg919Gly and p.Thr935Met showed some correlations to phenotype. The p.Arg778Leu was related to younger onset age and lower levels of ceruloplasmin (Cp) and serum copper, while p.Arg919Gly and p.Thr935Met both indicated higher Cp levels. Besides, the p.Arg919Gly was related to neurological subtype, and p.Thr935Met showed significant difference in the percentage of combined neurological and visceral subtype. Moreover, for ATP7B mutations, the more severe impact on ATP7B protein was, the younger onset age and lower Cp level presented. The feasibility of presymptomatic DNA diagnosis and predicting clinical manifestation or severity of WD would be facilitated with identified mutations and genotype-phenotype correlation precisely revealed in the study.

Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease

“…A relative high proportion of patients in this large WD cohort (21%) had only one detectable mutation, and similar data were reported by other studies . This is in contrast to the surprisingly 98%‐100% detection rate of two mutations in the much smaller studies .…”

“…A relative high proportion of patients in this large WD cohort (21%) had only one detectable mutation, and similar data were reported by other studies. (25)(26)(27) This is in contrast to the surprisingly 98%-100% detection rate of two mutations in the much smaller studies. (28,29) There are several differences compared with our study that can explain the observed differences in mutation detection rate-most importantly, the lack of a clinical description of the patients in the UK study.…”

Biochemical and molecular characterisation of neurological Wilson disease

“…In patients with untreated WD, serum copper and ceruloplasmin levels are decreased with increased urinary copper excretion, and the free copper level may increase to more than 25 µg/dL 2. In a previous study, the serum ceruloplasmin level is lower in the neurological subgroup (<8 mg/dL) than in the hepatic subgroup 13. In the present study, all biochemical values involved in copper metabolism, including serum and free copper, ceruloplasmin, and urinary copper excretion levels, were decreased in the neurological subgroup.…”

Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants

“…In Asia, p.R778L (c.2333 G > T, exon 8) has been identified as the most common ATP7B variant, with a frequency of 17.3–31.9% reported in China (Cheng et al, ; X. H. Li et al, ; Mak et al, ; Wan et al, ). However, WD also exhibits genetic heterogeneity, as several studies have reported a much higher frequency of heterozygotes than homozygotes (Cheng et al, ; Hua et al, ; Xie & Wu, ). WD was initially considered to be a recessive genetic disorder but this is inconsistent with the high frequency of heterozygous mutations identified, of which the effects on ATP7B are mostly unknown.…”

“…Most previous studies have focused on either unrelated individuals (Cheng et al, ; Coffey et al, ; Y. Dong et al, ) or case reports or series of a limited number of pedigrees (Dufernez et al, ; Yuan et al, ; Zhang et al, ); moreover, direct experimental evidence of the functional consequences of individual ATP7B variants is still lacking. Here, to perform a systemic analysis of the genotypes of WD patients in China, we recruited 65 Chinese WD patients from 60 families for DNA sequencing.…”