Linked Life Data

18203200

Source:http://linkedlifedata.com/resource/pubmed/id/18203200

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2008-3-17
pubmed:abstractText
ATP7B is a copper transporting P-type ATPase defective in the autosomal recessive copper storage disorder, Wilson disease (WND). Functional assessment of variants helps to distinguish normal from disease-causing variants and provides information on important amino acid residues. A total of 11 missense variants of ATP7B, originally identified in WND patients, were examined for their capacity to functionally complement a yeast mutant strain in which the yeast gene ortholog, CCC2, was disrupted. Solution structures of ATP7B domains were used to predict the effects of each variant on ATP7B structure. Three variants lie within the copper-binding domain and eight within the ATP-binding domain of ATP7B. All three ATP7B variants within the copper-binding domain and four within the ATP-binding domain showed full complementation of the yeast ccc2 phenotype. For the remaining four located in the ATP-binding domain, p.Glu1064Lys and p.Val1106Asp were unable to complement the yeast ccc2 high-affinity iron uptake deficiency phenotype, apparently due to mislocalization and/or change in conformation of the variant protein. p.Leu1083Phe exhibited a temperature-sensitive phenotype with partial complementation at 30 degrees C and a severe deficit at 37 degrees C. p.Met1169Val only partially complemented the ccc2 phenotype at 30 degrees C and 37 degrees C. Therefore, four variant positions were identified as important for copper transport and as disease-causing changes. Since the yeast assay specifically evaluates copper transport function, variants with normal transport could be defective in some other aspect of ATP7B function, particularly trafficking in mammalian cells. Functional assessment is critical for reliable use of mutation analysis as an aid to diagnosis of this clinically variable condition.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1098-1004
pubmed:author
pubmed:copyrightInfo
Copyright 2008 Wiley-Liss, Inc.
pubmed:issnType
Electronic
pubmed:volume
29
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
491-501
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:18203200-Adenosine Triphosphatases, pubmed-meshheading:18203200-Adenosine Triphosphate, pubmed-meshheading:18203200-Binding Sites, pubmed-meshheading:18203200-Cation Transport Proteins, pubmed-meshheading:18203200-Ceruloplasmin, pubmed-meshheading:18203200-Copper, pubmed-meshheading:18203200-Genetic Complementation Test, pubmed-meshheading:18203200-Genetic Variation, pubmed-meshheading:18203200-Hepatolenticular Degeneration, pubmed-meshheading:18203200-Humans, pubmed-meshheading:18203200-Ion Transport, pubmed-meshheading:18203200-Models, Biological, pubmed-meshheading:18203200-Models, Molecular, pubmed-meshheading:18203200-Mutation, Missense, pubmed-meshheading:18203200-Phenotype, pubmed-meshheading:18203200-Protein Conformation, pubmed-meshheading:18203200-Protein Structure, Tertiary, pubmed-meshheading:18203200-Recombinant Proteins, pubmed-meshheading:18203200-Saccharomyces cerevisiae, pubmed-meshheading:18203200-Saccharomyces cerevisiae Proteins
pubmed:year
2008
pubmed:articleTitle
Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system.
pubmed:affiliation
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't