Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson’s disease

Gromadzka, Grażyna; Magdalena, Rudnicka; Chabik, Grzegorz; Przybyłkowski, Adam; Członkowska, Anna

doi:10.1016/j.jhep.2011.01.030

Cited by 49 publications

(31 citation statements)

References 38 publications

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“…This is consistent with previous reports that the p.Arg778Leu mutation is related to a later onset of disease with neurological manifestations, or an early onset with severe liver disease [36]. The variable clinical manifestations of patients 3 and 4 imply that the development of WD may not only be influenced by ATP7B mutations, but also modifier genes [37,38], epigenetics [39], dietary copper intake, capability for processing copper stress, and metallothionein inducibility [40]. The ATP7B gene, located on 13q14.3 [16,41], encodes a copper transporter of 1,465 amino acids [42].…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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

Xiao

Deng

et al. 2018

Digestion

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“…All of patients had hepatic diseases, whereas only 60% (12/20) of patients had neurological presentations as the early manifestations. Although the hepatic presentation was assumed to mean more severely deranged ATP7B function, modifier genes, such as the 5,10-methylenetetrahydrofolate reductase gene, environmental factors, such as nutritional copper intake, infectious disease, drug and toxin, and other epigenetic factors must be at play in the overall phenotypic expression of WD in individuals [15], [16]. We found three homozygous ATP7B mutations and 15 compound heterozygous mutations in 2 consanguinity pedigrees and 16 non-consanguinity pedigrees, respectively.…”

Section: Discussionmentioning

confidence: 80%

Novel ATPase Cu2+ Transporting Beta Polypeptide Mutations in Chinese Families with Wilson's Disease

Yang

et al. 2013

PLoS ONE

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Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu2+ transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.

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“…Genetic modifiers such as the presence of an E4 allele of apolipoprotein E (ApoE) or polymorphisms in the methylenetetrahydrofolate reductase gene ( MTHFR ) may contribute to age of WD onset but these studies await confirmation in larger, independent populations. 16, 17 …”

Section: Geneticsmentioning

confidence: 99%

Wilson's disease and other neurological copper disorders

Bandmann

Weiss

Kaler

2015

The Lancet Neurology

744

534

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Summary The classic copper metabolism disorder, Wilson disease (WD), was first defined in 1912. Both early onset presentations in infancy and late onset manifestations in adults > 70 years are now well recognized. Modern biochemical and genetic prevalence studies suggest that WD may be considerably more common than previously appreciated. Early diagnosis of WD is crucial to ensure that patients can be started on adequate treatment but uncertainty remains about the best possible choice of medication. Direct genetic testing for ATP7B mutations is increasingly available to confirm the clinical diagnosis of WD. WD needs to be differentiated from other conditions that present clinically with hepatolenticular degeneration or share biochemical abnormalities with WD, such as reduced serum cerulo plasmin levels. Disordered copper metabolism is also implied in an increasing number of other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations, and the common late-onset neurodegenerative disorders Alzheimer’s disease and Parkinson’s disease.

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Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson’s disease

Cited by 49 publications

References 38 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

Novel ATPase Cu2+ Transporting Beta Polypeptide Mutations in Chinese Families with Wilson's Disease

Wilson's disease and other neurological copper disorders

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