Mutational characterization of ATP7B gene in 103 Wilson’s disease patients from Southern China

Abstract

Wilson's disease (WD) is an autosomal recessive inheritance disorder of copper metabolism due to mutations in the ATP7B gene. The distribution of ATP7B gene mutations is diverse in different population. This study aimed to examine the genotypes of the ATP7B mutant alleles in WD patients from Southern China. Genomic DNA was extracted from 103 WD patients and 60 healthy patients. Mutations were screened and detected by DNA sequencing. A total of 51 different ATP7B mutations were identified in WD patients, including six homozygous, 51 compound heterozygous, and 39 single heterozygotes. Three mutations were found to be novel, including one missense mutation (c.2549C>T) and two frameshift mutations (c.3851_3876del and c.1057delC). The most frequent mutations are Arg778Leu (18.93%), Ile1148Thr (8.74%), and Pro992Leu (4.37%). Different from the published results of early studies, Ile1148Thr was found to be the second common mutation in our cohort. The highest mutation detection rate was on exon 8 (43.69%), followed by exon 16 (24.27%), and exon 12 (17.48%). The total mutation detection rate on exon 8, 12, and 16 was 85.44%. No ATP7B gene mutation was found in healthy patients. In conclusion, we identified three novel mutations and Ile1148Thr as another hotspot mutation in WD patients from Southern China. Most of the mutations can be detected by screening exon 8, 12, and 16. Our research has further enriched the mutation spectrum of the ATP7B gene in Chinese and may help to develop genetic screening strategies of WD.

Study on Lesion Assessment of Cerebello-Thalamo-Cortical Network in Wilson’s Disease with Diffusion Tensor Imaging

“…Alterations in the gene, which is responsible for the synthesis of protein P-type ATPase (ATP7B), lead to pathological copper accumulation, especially in the liver and the brain [2]. Copper accumulation usually causes severe clinical manifestations, including liver failure, hepatitis [3], cirrhosis [4], premature death [5], and motor [6], emotion, cognitive impairments [7].…”

Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease

“…Mutation hotspots in ATP7B vary by geographic region, with a higher prevalence of specific variants reported in certain populations. The predominant variants in the Chinese population include c.2333G>T (p.Arg778Leu), c.2975C>T (p.Pro992Leu), c.3443T>C (p.Ile1148Thr), and c.2804C>T (p.Thr935Met) (Gu et al, ; Wang et al, ; Wei et al, ). In our study, the most frequently observed DVs were c.2333G>T, c.2304dupC, c.2621C>T, c.588C>A, c.1708‐5T>G, c.2827G>A, c.2975C>T, c.3053C>T, c.3646G>A, c.A3809A>G, and c.4114C>T. The one silent variant was c.2310C>G. The two uncertain variants (DVs or NDVs) were c.3316G>A and c.3443T>C.…”

“…Mutation hotspots in ATP7B vary by geographic region, with a higher prevalence of specific variants reported in certain populations. The predominant variants in the Chinese population include c.2333G>T (p.Arg778Leu), c.2975C>T (p.Pro992Leu), c.3443T>C (p.Ile1148Thr), and c.2804C>T (p.Thr935Met) (Gu et al, 2003;Wang et al, 2011;Wei et al, 2014). In our study, the most frequently observed In our study, we found six novel variants, of which two were synonymous mutations (c.1875T>A and c.3243G>A) and four were possible DVs (c.2306T>C, c.3028A>G, c.3437_3438 delTG, and c.3903+5G>A).…”

Development and evaluation of an unlabeled probe high-resolution melting assay for detection of ATP7B mutations in Wilson's disease

“…Among these mutations, p.Arg778Leu (c.2333G>T) has been identified as the most common. Both p.Pro992Leu (c.2975C>T) and p.Val1106Ile (c.3317G>A) are also relatively frequent mutations in WD, and also play important roles in the detection of WD …”

“…Both p.Pro992Leu (c.2975C>T) and p.Val1106Ile (c.3317G>A) are also relatively frequent mutations in WD, and also play important roles in the detection of WD. [5][6][7] Various approaches have been described for the detection of ATP7B gene mutations, such as multi-allele genotyping, genotyping microarray, and Sanger sequencing, but the clinical uses of these approaches are limited. 8,9 Recently, high-resolution melting (HRM) analysis was developed as a closed-tube technology for genotyping DNA variants and mutation screening, with advantages over other techniques such as its high-throughput, rapid, and nondestructive nature.…”