Splicing Mutations in KCNQ1

• DOI: 10.1161/01.cir.100.10.1077
• Publication Date: 2012-06-12T00:42:29Z
• Authors: A. Murray; C. Donger; C. Fenske; I. Spillman; P. Richard; Y. B. Dong; N. Neyroud; P. Chevalier; I. Denjoy; N. Carter; P. Syrris; A. R. Afzal; M. A. Patton; P. Guicheney; S. Jeffery
• Keywords: splice; Splice site mutation; Sudden Death

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