Genotype phenotype correlation in Wilson’s disease within families-a report on four south Indian families

Santhosh, Sam; Shaji, R. V.; Eapen, CE; Jayanthi, V.; Malathi, S.; Finny, P; Nicolaï, Thomas; Chandy, Mammen; Kurian, George; Chandy, GM

doi:10.3748/wjg.14.4672

Cited by 21 publications

(13 citation statements)

References 18 publications

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“…This observation is consistent with the designation of c2623A/G as a polymorphism, which was made in genetic studies of the Han Chinese population (7). In the Indian population, however, Arg 875 is a WD-causing mutation (8). To identify reasons for this dual behavior, we investigated the intracellular targeting and activity of ATP7B-Arg 875 under various conditions.…”

supporting

confidence: 53%

Cellular copper levels determine the phenotype of the Arg ⁸⁷⁵ variant of ATP7B/Wilson disease protein

Gupta¹,

Bhattacharjee²,

Dmitriev

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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In human disorders, the genotype-phenotype relationships are often complex and influenced by genetic and/or environmental factors. Wilson disease (WD) is a monogenic disorder caused by mutations in the copper-transporting P-type ATPase ATP7B. WD shows significant phenotypic diversity even in patients carrying identical mutations; the basis for such diverse manifestations is unknown. We demonstrate that the 2623A/G polymorphism (producing the Gly 875 →Arg substitution in the A-domain of ATP7B) drastically alters the intracellular properties of ATP7B, whereas copper reverses the effects. Under basal conditions, the common Gly 875 variant of ATP7B is targeted to the trans-Golgi network (TGN) and transports copper into the TGN lumen. In contrast, the Arg 875 variant is located in the endoplasmic reticulum (ER) and does not deliver copper to the TGN. Elevated copper corrects the ATP7B-Arg 875 phenotype. Addition of only 0.5-5 μM copper triggers the exit of ATP7B-Arg 875 from the ER and restores copper delivery to the TGN. Analysis of the recombinant A-domains by NMR suggests that the ER retention of ATP7B-Arg 875 is attributable to increased unfolding of the Arg 875 -containing A-domain. Copper is not required for the folding of ATP7B-Arg 875 during biosynthesis, but it stabilizes protein and stimulates its activity. A chemotherapeutical drug, cisplatin, that mimics a copper-bound state of ATP7B also corrects the "disease-like" phenotype of ATP7B-Arg 875 and promotes its TGN targeting and transport function. We conclude that in populations harboring the Arg 875 polymorphism, the levels of bioavailable copper may play a vital role in the manifestations of WD.trafficking | cisplatin | phenotypic variability

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supporting

confidence: 53%

Cellular copper levels determine the phenotype of the Arg ⁸⁷⁵ variant of ATP7B/Wilson disease protein

Gupta¹,

Bhattacharjee²,

Dmitriev

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The c.3028A>G（AAG‐GAG, p.Lys1010Glu）mutation is regarded as a new DV. At the same amino acid position, three DVs have been verified previously (Santhosh et al, ). It is found a compound heterozygote patient carrying c.3028A>G mutation and the known pathogenic variant c.3053C>T. We found a novel variant in exon 16, c.3437_3438 delTG (p.Val1146Ala fs*6).…”

Section: Discussionsupporting

confidence: 59%

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

Qian

Huang

Liu

et al. 2019

Molec Gen & Gen Med

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Background Wilson's disease (WD) is an autosomal recessive genetic disease caused by mutations in ATP7B and characterized by copper metabolism disorders. Methods Direct sequencing of the ATP7B gene is the most sensitive and widely used confirmatory testing method. Fourteen probands with WD and 12 family members participated in this study. The ATP7B gene was analyzed by direct sequencing. Results Twenty‐nine different variants (27 substitutions, 1 duplication, 1 deletion) were found. Of the 23 reported variants, nine nondisease variants, 11 disease variants, one silent variant, and two variants with uncertain functions were identified. The six novel variants included c.1875T>A, c.2306T>C, c.3028A>G, c.3243G>A, c.3437_3438 delTG, and c.3903+5G>A. Conclusion These findings will assist in the diagnosis of WD. The novel variants have enriched the WD database.

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“…Case studies have reported twins and siblings who have the same WD genotype presenting with disparate phenotypes— implicating factors other than genetics, including epigenetics, 97–100 in the presentation of WD. 101 Animal studies in the Jackson toxic milk (tx-j) mouse model of WD support this model, 102 astx-j mice show DNA hypomethylation and altered expression of genes that are involved in DNA methylation compared with wild-type mice.…”

Section: Evidence Of Epigenetic Regulation In Wilson Diseasementioning

confidence: 99%

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Kieffer

Medici

2017

Liver Research

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Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the “multi-hit” hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent “hits” are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.

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Genotype phenotype correlation in Wilson’s disease within families-a report on four south Indian families

Cited by 21 publications

References 18 publications

Cellular copper levels determine the phenotype of the Arg ⁸⁷⁵ variant of ATP7B/Wilson disease protein

Cellular copper levels determine the phenotype of the Arg ⁸⁷⁵ variant of ATP7B/Wilson disease protein

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

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

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Genotype phenotype correlation in Wilson’s disease within families-a report on four south Indian families

Cited by 21 publications

References 18 publications

Cellular copper levels determine the phenotype of the Arg 875 variant of ATP7B/Wilson disease protein

Cellular copper levels determine the phenotype of the Arg 875 variant of ATP7B/Wilson disease protein

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

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

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Product

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Cellular copper levels determine the phenotype of the Arg ⁸⁷⁵ variant of ATP7B/Wilson disease protein

Cellular copper levels determine the phenotype of the Arg ⁸⁷⁵ variant of ATP7B/Wilson disease protein