Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort

Lee, Beom H.; Kim, Joo H.; Lee, Sun Young; Jin, Hye Young; Kim, Kwi-Joo; Lee, Jin-Joo; Park, Jung-Young; Kim, Gu-Hwan; Choi, Jin–Ho; Kim, Kyung Mi; Yoo, Han‐Wook

doi:10.1111/j.1478-3231.2011.02503.x

Cited by 56 publications

(52 citation statements)

References 40 publications

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“…Consistently, the onset age of our patients (combined with our previous data) with protein-truncating mutations ranges from 2 to 20 years old (mean onset age: 12.3 ± 5.9 years old), while that of our patients with missense mutations ranges from 6 to 41 years old (mean onset age: 19.9 ± 10.9 years old) [22]. Mutations in the transduction domain (Td) and the ATP hinge domain were associated with patients having presymptomatic or hepatic manifestations but no neurological presentations [35]. However, in this study, patients (2, 5, 6, and 7) having one mutation located in the Td or the ATP hinge domain showed neurological symptoms, indicating that the variable clinical manifestations may be resulted from a combined effect of compound heterozygous mutations located in different domains of the ATP7B gene.…”

Section: Discussionmentioning

confidence: 99%

“…Because of the highly variable phenotypic heterogeneities in WD [35], diagnosis of WD based solely on clinical manifestations and conventional biochemical indices is not always reliable or convincing [35,40]. Failure to diagnose patients may lead to a reduced number of clinically diagnosed WD patients and even death [5].…”

Section: Discussionmentioning

confidence: 99%

“…It is likely to impair the protein function by affecting the secondary structure of the ATP loop [48]. The mutation p.Ala1295Val replaces the amino acid alanine in the conserved ATP hinge domain with valine [22], which may cause functional perturbation as p.Ala1295Asp [35].…”

Section: Discussionmentioning

confidence: 99%

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Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease

Xiao

Deng

et al. 2018

Digestion

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Background: Wilson’s disease (WD) is an autosomal recessive disease, which is characterized by an excessive copper accumulation in the liver and brain, leading to subsequent hepatic and/or neurological disorders. The causative gene for WD has been identified as the ATPase Cu²⁺ transporting beta polypeptide gene (ATP7B), which encodes a protein called copper-transporting ATPase 2. ATP7B mutations may lead to reduced biliary excretion of excess copper and disrupted copper homeostasis, resulting in various clinical symptoms of WD. Methods: Direct sequencing of the ATP7B gene was performed in 7 Han Chinese families with WD, and haplotype analysis was conducted in families having the same mutation. Results: Nine ATP7B gene mutations were identified, including 7 missense mutations (p.Asp765Gly, p.Arg778Leu, p.Thr888Pro, p.Pro992Leu, p.Asp1047Val, p.Ile1148Thr and p.Ala1295Val), 1 duplication mutation (c.525dupA), and 1 nonsense mutation (p.Gly837*). Combined with our previous data, haplotype analysis revealed that the founder effect accounted for 48% of alleles in Han Chinese, constituted by high allele frequency mutations p.Arg778Leu, p.Pro992Leu and p.Ala1295Val. Conclusion: This study revealed genetic defects of 7 Han Chinese families with WD, and has implications for their genetic counseling and clinical management.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease

Xiao

Deng

et al. 2018

Digestion

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“…In different populations, individuals with no mutations have been reported in different proportions (16)(17)(18)(19)(20). Failure to detect any mutations may be explained by unknown mutations that may be located on the outside of the exons and flanking regions, such as the promoter, introns, or other DNA control regions (16,19 Table 2. Distribution of single nucleotide polymorphisms detected in the entire coding region of the ATP7B gene tients who have no mutation in the ATP7B gene, additional research is necessary.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic analysis of pediatric patients with Wilson disease

Papur¹,

Akman²,

Terzioğlu³

2015

Turk J Gastroenterol

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Background/Aims: Wilson disease (WD, MIM# 277900) is an autosomal recessive disorder of copper transport resulting from the defective function of a copper transporting P-type ATPase. Detecting mutations and single nucleotide polymorphisms (SNPs) of the ATP7B gene in Turkish pediatric WD patients (n=32) and controls (n=52) is the aim of this research. Materials and Methods: For screening mutations and SNPs of the ATP7B gene, sequencing was performed. Results: Mutations were determined in the ATP7B gene in 23 out of the 32 pediatric patients. The mutation detection rate in the ATP7B gene of the pediatric Turkish WD patients was 71.875%. Fifteen different mutations were determined in the ATP7B gene. These mutations were distributed throughout the ATP7B gene and were as follows: 2 deletion, 1 insertion, 3 nonsense, and 9 missense mutations. Four of these, including c.3111delC (1 deletion) and c.2363C>T, c.3733C>A, and c.3451C>T (3 missense) mutations, were detected in the Turkish WD patients. Eleven polymorphisms were detected in both groups. Among these, c.3727G>A (SNP) was reported in the Wilson Disease Mutation Database by our group. Nine out of the thirty-two pediatric Turkish WD patients had no mutations in the ATP7B gene. Conclusion: To find the cause of WD in pediatric patients who have no mutation in ATP7B, additional research is necessary.

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“…Although the form of the disease initially described was predominantly neurological [1] , the disease manifestations can be pleomorphic, and although the correlation mutation-predominant manifestation has been elusive [23,24] , clinical forms of the disease tend to cluster and wide geographical differences exist [25] . Thus, WD may be predominantly hepatic, neurological or psychiatric, and manifestations of disease may range from an asymptomatic state to life-threatening fulminant hepatic failure [26][27][28][29][30] .…”

Section: Clinical Manifestationsmentioning

confidence: 99%

Wilson’s disease: A review of what we have learned

Rodríguez–Castro

Hevia‐Urrutia

Sturniolo

2015

WJH

124

121

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Wilson's disease (WD), which results from the defective ATP7B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.

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Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort

Abstract: The presenting phenotype strongly affects the clinical outcome of WD, and is related to the ATP7B mutation type and location, providing an evidence for genotype-phenotype correlations in WD.

Cited by 56 publications

References 40 publications

Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease

Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease

Clinical and genetic analysis of pediatric patients with Wilson disease

Wilson’s disease: A review of what we have learned

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