Linked Life Data

12354768

Source:http://linkedlifedata.com/resource/pubmed/id/12354768

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
50
pubmed:dateCreated
2002-12-9
pubmed:abstractText
The congenital long QT syndrome is a cardiac disease characterized by an increased susceptibility to ventricular arrhythmias. The clinical hallmark is a prolongation of the QT interval, which reflects a delay in repolarization caused by mutations in cardiac ion channel genes. Mutations in the HERG (human ether-à-go-go-related gene KCNH2 can cause a reduction in I(Kr), one of the currents responsible for cardiac repolarization. We describe the identification and characterization of a novel missense mutation T65P in the PAS (Per-Arnt-Sim) domain of HERG, resulting in defective trafficking of the protein to the cell membrane. Defective folding of the mutant protein could be restored by decreased cell incubation temperature and pharmacologically by cisapride and E-4031. When trafficking was restored by growing cells at 27 degrees C, the kinetics of the mutated channel resembled that of wild-type channels although the rate of activation, deactivation, and recovery from inactivation were accelerated. No positive evidence for the formation of heterotetramers was obtained by co-expression of wild-type with mutant subunits at 37 degrees C. As a consequence the clinical symptoms may be explained rather by haploinsufficiency than by dominant negative effects. This study is the first to relate a PAS domain mutation in HERG to a trafficking deficiency at body temperature, apart from effects on channel deactivation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
48610-6
pubmed:dateRevised
2008-10-28
pubmed:meshHeading
pubmed-meshheading:12354768-Adult, pubmed-meshheading:12354768-Amino Acid Sequence, pubmed-meshheading:12354768-Base Sequence, pubmed-meshheading:12354768-Blotting, Western, pubmed-meshheading:12354768-Cation Transport Proteins, pubmed-meshheading:12354768-Cell Line, pubmed-meshheading:12354768-DNA Primers, pubmed-meshheading:12354768-DNA-Binding Proteins, pubmed-meshheading:12354768-Ether-A-Go-Go Potassium Channels, pubmed-meshheading:12354768-Female, pubmed-meshheading:12354768-Humans, pubmed-meshheading:12354768-Long QT Syndrome, pubmed-meshheading:12354768-Male, pubmed-meshheading:12354768-Microscopy, Confocal, pubmed-meshheading:12354768-Molecular Sequence Data, pubmed-meshheading:12354768-Mutagenesis, Site-Directed, pubmed-meshheading:12354768-Mutation, Missense, pubmed-meshheading:12354768-Pedigree, pubmed-meshheading:12354768-Potassium Channels, pubmed-meshheading:12354768-Potassium Channels, Voltage-Gated, pubmed-meshheading:12354768-Sequence Homology, Amino Acid, pubmed-meshheading:12354768-Trans-Activators
pubmed:year
2002
pubmed:articleTitle
A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.
pubmed:affiliation
Department of Pharmacogenomics, Johnson & Johnson Pharmaceutical Research and Development, Beerse B-2340, Belgium. paulussen.aimee@advalvas.be
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't