Novel mutations of the ATP7B gene in Han Chinese families with pre-symptomatic Wilson’s disease

Yuan, Zhao-Feng; Wu, Wei; Yang, Yu; Shen, Jue; Mao, Shanshan; Gao, Feng; Xia, Zhezhi

doi:10.1007/s12519-015-0031-5

Cited by 12 publications

(16 citation statements)

References 24 publications

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“…Although a variety of ATP7B mutations were identified in the WD patients in our study, the majority of these were heterozygous, and fewer homozygous mutations were identified. Most previous studies on WD 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, ). In the current pedigree analysis, we found only eight patients with a homozygous mutation, and most of the patients (43/65) harbored two or more heterozygous mutations on different alleles.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Zhou

et al. 2019

Human Mutation

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Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. In this study, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Pedigree analysis showed that besides several ATP7B homozygous variants (8/65, 12.3%), compound heterozygous variants (43/65, 66.2%) were present in the majority of WD patients. There were 20% of the patients had one (12/65, 18.5%) or multiple (1/65, 1.5%) variants in only a single allele, characterized by a high ratio of splicing or frameshift variants. Nine ATP7B variants were cloned into the pAG426GPD yeast expression vector to evaluate their functional consequences, and the results suggested different degrees of functional disruption from mild or uncertain to severe, consistent with the corresponding phenotypes. Our study revealed the complex ATP7B mutation patterns in WD patients and the applicability of a yeast model system to the Human Mutation. 2019;40:552-565. wileyonlinelibrary.com/journal/humu 552 |

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhang

Zhou

et al. 2019

Human Mutation

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“…The p.(Asn728Ser) missense mutation was first reported by Yuan et al. in 2015 after screening a 5‐year‐old Chinese patient with a neurological disorder (Yuan et al., ). The higher prevalence of this mutation was observed in the present study with 8% frequency, which is connotative of another common mutation in Indian population; however, it was never reported earlier from this region.…”

Section: Discussionmentioning

confidence: 99%

“…(Butler, McIntyre, & Mistry, 2001;Kumar et al, 2005;Tomić et al, 2013). The p.(Asn728Ser) missense mutation was first reported by Yuan et al in 2015 after screening a 5-year-old Chinese patient with a neurological disorder (Yuan et al, 2015). The higher prevalence of this mutation was observed in the present study with 8% frequency, which is connotative of another common mutation in Indian population; 2865+1G>A is a rare mutation having one incidence each from the Czech Republic and Western India (1%) (Aggarwal et al, 2013;Vrabelova, Letocha, Borsky, & Kozak, 2005), p.(Trp1153Arg), present in the European population (Waldenström, Lagerkvist, Dahlman, Westermark, & Landegren, 1996), is the first time being reported from India in this study.…”

Section: Discussionmentioning

confidence: 99%

Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications

Kumari

Kumar

Thapa³

et al. 2018

Human Mutation

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Wilson disease (WD), a copper metabolism disorder, occurs due to the presence of mutations in the gene encoding ATP7B, a protein that primarily facilitates hepatic copper excretion. A better understanding of spectrum and functional significance of ATP7B variants is critical to formulating targeted and personalized therapies. Henceforth, we screened and sequenced 21 exons of ATP7B gene from 50 WD patients and 60 healthy subjects. We identified 28 variants comprising, seven novels in 20% alleles, while eight variations affecting 23% alleles were first time reported in Indian cohort. The c.813C>A, p.(Cys271*) (10%) was the most frequent mutation. Bioinformatics analysis revealed five of seven novel variants viz. c.1600C>A, p.(Pro534Thr); c.1616C>A, p.(Pro539His); c.1924G>T, p.(Asp642Tyr); c.2168G>C, p.(Arg723Thr); c.2174G>C, p.(Arg725Thr) resulted in protein misfolding. Sequence conservation analysis of ATP7B regions containing novel variants documented an evolutionarily conserved nature. Functional analysis of these novel variants in five different cell lines lacking inherent ATP7B expression demonstrated sensitivity to CuCl -treatment, experiencing augmented cellular copper retention and decreased copper excretion as well as ceruloplasmin secretion to that of wildtype-ATP7B expressing cells. Interestingly, pharmacological chaperone 4-phenylbutyrate, a clinically approved compound, partially restored protein function of ATP7B mutants. These findings might enable novel treatment strategies in WD by clinically enhancing the protein expression of mutant ATP7B with residual copper export activity.

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“…The copper-binding AT-phase, coded by ATP7B gene is a group of transmembrane transport proteins of copper, mediating its metabolism. For the present, 600 pathogenic mutations are revealed in ATP7B gene, and new ones are continuously found throughout the world [3,4].…”

Section: Introductionmentioning

confidence: 99%

Genetic Diagnostics and Clinical Features of Wilson’s Disease in Children

Haiboniuk

Dats-Opoka

Makukh

et al. 2020

EUREKA: Life Sciences

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A disorder of copper metabolism at Wilson's disease (WD), conditioned by a mutation of adenosine thriphospate P-type gene (ATP7B), results in irreversible changes in the liver and in the nervous system. Mortality is high at WD, but it is one of hereditary diseases, well subjected to the therapy. The disease is manifested in the early age, but its clinical course in children is symptomless that essentially complicates diagnostics. A single reliable method is genetic analysis for revealing mutations in ATP7B gene. The aim of the work was to analyze clinical manifestations and course of Wilson's disease cases, genetically verified in children by detecting mutations of ATP7B gene. The research group included children of 6-17 years old with different injury degrees of the hepatobiliary system. According to results of the molecular-genetic analysis, the most spread allele variant of ATP7B gene (H1069Q) in Europe was confirmed in 10 patients of child age, including 4 cases of homozygosity. In 10 cases of the confirmed diagnosis of Wilson's disease in child age in 100 % (in all 10) of persons, a clinical manifestation was characterized by disorders from the hepatobiliary system, and only in 1 (10 %)-changes from the nervous system. At raising the level of transaminase in children, even at the normal bilirubin level and negative tests for viral hepatitis, it is recommended to carry out genetic testing for Wilson's disease.

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Novel mutations of the ATP7B gene in Han Chinese families with pre-symptomatic Wilson’s disease

Cited by 12 publications

References 24 publications

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

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

Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications

Genetic Diagnostics and Clinical Features of Wilson’s Disease in Children

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