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Splicing mutations in KCNQ1 - A mutation hot spot at codon 344 that produces in frame transcripts.
1077 - 1084.
Background-Long-QT syndrome is a monogenic disorder that produces cardiac arrhythmias and can lead to sudden death. At least 5 loci and 4 known genes exist in which mutations have been shown to be responsible for the disease. The potassium channel gene KCNQ1, previously named KVLQT1, on chromosome 11p15.5 is one of these.Methods and Results-We initially analyzed one family using microsatellite markers and found linkage to KCNQ1. Mutation detection showed a G to C change in the last base of exon 6 (1032 G-->C) that does not alter the coded alanine, Restriction digest analysis in the family showed that only affected individuals carried the mutation. A previous report suggested that a G to A substitution at the same position may act as a splice mutation in KCNQ1, but no data was given to support this hypothesis nor was the transcription product identified. We have shown by reverse-transcription polymerase chain reaction that 2 smaller bands were produced for the KCNQ1 gene transcripts in addition to the normal-sized transcripts when lymphocytes of affected individuals were analyzed. Sequencing these transcripts showed a loss of exon 7 in one and exons 6 and 7 in the other, but an in-frame transcript was left in each instance. We examined other families in whom long-QT syndrome was diagnosed and found another unreported splice-site mutation, 922-1 G-->C in the acceptor site of intron 5, and 2 of the previously reported 1032 G-->A mutations. All these showed a loss of exons 6 and 7 in the mutant transcripts, validating the proposal that a consensus sequence is affected in the exonic mutations and that the integrity of the base at position 1032 is essential for correct processing of the transcript.Conclusions-The 6 cases already reported in the literature with the 1032 G-->A transition, the novel 1032 G-->C transversion, and a recent G-->T transversion at the same base show that codon 344 is the second most frequently mutated after codon 341, suggesting at least two hotspots for mutations in KCNQ1.
|Title:||Splicing mutations in KCNQ1 - A mutation hot spot at codon 344 that produces in frame transcripts|
|Keywords:||long-QT syndrome, mutation, ion channels, LONG-QT-SYNDROME, LANGE-NIELSEN-SYNDROME, CARDIAC POTASSIUM CURRENT, PHENOTYPIC-EXPRESSION, GENOMIC ORGANIZATION, KVLQT1 MUTATIONS, CAUSE JERVELL, CHANNEL GENE, ROMANO-WARD, ISK|
|UCL classification:||UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
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