Identification and molecular characterization of 18 novel mutations in the <i>ATP7B</i> gene from Indian Wilson disease patients: genotype

Kumar, Sunil; Br, Thapa; Kaur, Gurjit; Prasad, Rajendra

doi:10.1111/j.1399-0004.2005.00440.x

Cited by 35 publications

(15 citation statements)

References 10 publications

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“…Greece, Saudi Arabia, Serbia, etc. (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).…”

Section: Discussionmentioning

confidence: 99%

“…Serum ceruloplasmin activity was measured as copper oxidase using p-phenylenediamine dihydrochloride as substrate. Serum copper and 24-hour urine copper were estimated using atomic absorption spectrophotometer as described previously (Kumar et al, 2005;Prasad, Kaur, & Walia, 1998). Presence of KF rings was evaluated by ophthalmologists.…”

Section: Subjects and Sample Collectionmentioning

confidence: 99%

“…PCR fragments were subjected to single strand conformation polymorphism (SSCP) as described elsewhere (Kumar et al, 2005).…”

Section: Genetic Analysis Of Atp7b Genementioning

confidence: 99%

“…Moreover, Indian WD population is prone to develop the disease at a younger age in comparison to western WD population, which further makes the management of the disease difficult and demands development of newer, personalized therapies. Various genetic studies previously reported from the region involved small WD patients, indicating the need for an extensive analysis (Aggarwal et al, 2013;Gupta et al, 2005Gupta et al, , 2007Kumar, Thapa, Kaur, & Prasad, 2005;Santhosh et al, 2006). In addition, the impact of many mutations on functional aspects of ATP7B gene is unknown.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Subjects and Sample Collectionmentioning

confidence: 99%

“…PCR fragments were subjected to single strand conformation polymorphism (SSCP) as described elsewhere (Kumar et al, 2005).…”

Section: Genetic Analysis Of Atp7b Genementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…The frequency of various mutations, correlated with regional differences, shows the data from India is quite divergent, reflecting the ethnic diversity of this large country. The most common mutations in patients, mostly from North-West India, are located on exons 8, 12, 13, 15, 16 and 18 (6, 14). A p.N1270S mutation however, is distinguished by its common occurrence in a large number of groups, including Chinese, Korean, Japanese, Indian, Sicilian, Bulgarian, Egyptian, Brazilian, Italian, Turkish, and American.…”

Section: Discussionmentioning

confidence: 99%

Hypercalciuria and Nephrocalcinosis as Early Feature of Wilson Disease Onset: Description of a Pediatric Case and Literature Review

Stefano¹,

Lionetti²,

Rotolo³

et al. 2012

Hepat Mon

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Background:Wilson’s disease (WD) is a rare autosomal-recessive disorder characterized by a mutation in the ATP7B gene, located on chromosome 13, which encodes a protein involved in the metabolism of copper.Case Presentation:We described the case of an Indian male with a history of polydipsia and polyuria, related to hypercalciuria and consequent nephrocalcinosis. The symptoms began at the age of five years old, but he was not diagnosed with WD until he reached an adolescent age. We started therapy with D-Penicillamine, B-vitamin complex and recommended a low copper diet. Renal involvement in Wilson’s disease, characterizing by hypercalciuria, was firstly reported by Litin in 1959.Conclusion:Our case was different and peculiar from the previously described cases because the patient presented a very long history (10 years) of permanent hypercalciuria without any acute episode of nephrolithiasis.

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Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B

et al. 2010

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Wilson disease (WND) is an autosomal recessive disorder resulting from mutation of ATP7B. Transport of copper by ATP7B from the trans-Golgi of hepatocytes into apical membrane-trafficked vesicles for excretion in the bile is the major means of copper elimination from the body. Although copper is an essential nutrient, homeostasis must be carefully maintained. If homeostasis is disrupted, copper can accumulate within the liver, kidney, cornea, and/or brain. The range of organs affected leads to clinical heterogeneity and difficulty in WND diagnosis. Sequencing of ATP7B is an important adjunct for diagnosis but has led to the discovery of many novel missense variants. Although prediction programs are available, functional characterization is essential for determining the consequence of novel variants. We have tested 12 missense variants localized to the ATP loop of ATP7B and compared three predictive programs (SIFT, PolyPhen, and Align-GVGD). We found p.L1043P, p.G1000R, p.G1101R, p.I1102T, p.V1239G, and p.D1267V deleterious; p.G1176E and p.G1287S intermediate; p.E1173G temperature sensitive; p.T991M and p.I1148T mild; and p.R1228T functioning as wild type. We found that SIFT most often agreed with functional data (92%), compared with PolyPhen (83%) and Align-GVGD (67%). We conclude that variants found to negatively affect function likely contribute to the WND phenotype in patients.

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Identification and molecular characterization of 18 novel mutations in the ATP7B gene from Indian Wilson disease patients: genotype

Cited by 35 publications

References 10 publications

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

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

Hypercalciuria and Nephrocalcinosis as Early Feature of Wilson Disease Onset: Description of a Pediatric Case and Literature Review

Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B

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