Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease

Wilson disease (WND), an autosomal recessive disorder of copper transport, is characterized by excessive accumulation of intracellular copper in liver and extrahepatic tissues because of impaired biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. Hepatic cirrhosis and...

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Bibliographic Details
Published in:Human mutation 2007-11, Vol.28 (11), p.1108-1113
Main Authors: Park, Sangwook, Park, Jung-Young, Kim, Gu-Hwan, Choi, Jin-Ho, Kim, Kyung-Mo, Kim, Jong-Bae, Yoo, Han-Wook
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - genetics
Adolescent
Adult
Alleles
Animals
Asymptomatic
ATP7B
Cation Transport Proteins - genetics
Cercopithecus aethiops
Child
Child, Preschool
Cloning
confocal microscopy
Copper
Copper-transporting ATPases
COS Cells
DNA, Complementary
Epstein-Barr virus
Gene Frequency
Hepatolenticular Degeneration - ethnology
Hepatolenticular Degeneration - genetics
Humans
Korea
Laboratories
Medical schools
Medicine
Microscopy
Middle Aged
Mutation
Pediatrics
Wilson disease
Yeast
yeast complementation system
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Summary:Wilson disease (WND), an autosomal recessive disorder of copper transport, is characterized by excessive accumulation of intracellular copper in liver and extrahepatic tissues because of impaired biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. Hepatic cirrhosis and neuronal degeneration are the major symptoms of WND, and mutations in the ATP7B gene are associated with WND. We have identified 28 different mutations in the ATP7B gene, including six novel variations, in 120 unrelated Korean patients with WND. Molecular defects in ATP7B were present in only 75.0% of Korean WND patients, with the most common mutation, p.Arg778Leu, having an allele frequency of 39.2%. To evaluate the functional defects of ATP7B caused by novel mutations, we used a yeast complementation system, and we used confocal microscopy to localize each mutation after transient expression in mammalian cells. Six novel variations were cloned into a yeast expression vector and two into a mammalian expression vector for confocal analysis. We found that c.2785A>G (p.Ile929Val) and c.3316G>A (p.Val1106Ile) were rare polymorphisms, whereas the others were novel variations disturbing ATP7B function. Hum Mutat 28(11), 1108-1113, 2007. © 2007 Wiley-Liss, Inc.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.20574