(Circulation. 1999;100:1077-1084.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Splicing Mutations in KCNQ1
A Mutation Hot Spot at Codon 344 That Produces In Frame Transcripts
From the Medical Genetics Unit, St George's Hospital Medical
School, London, England (A.M., C.F., Y.B.D., N.C., P.S., A.R.A., M.A.P.,
S.J.); INSERM U523 and IFR C
ur Muscle Vaisseaux, Hôpital
Pitié-Salpêtrière, Institut de Myologie, Paris, France
(C.D., N.N., P.G.); Paediatric Department, Macclesfield District General
Hospital, Macclesfield, England (I.S.); Service de Biochimie B and IFR
Cur Muscle Vaisseaux, Hôpital
Pitié-Salpêtrière, Paris (P.R.); Service de Cardiologie,
Hôpital Louis Pradel, Lyon (P.C.); and Service de Cardiologie,
Hôpital Lariboisière, Paris (I.D.), France.
Correspondence to S. Jeffery, Medical Genetics Unit, St George's Medical School, Cranmer Terrace, Tooting London, SW17 ORE, England.
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 GC, in the acceptor site of intron 5,
and 2 of the previously reported 1032 GA 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 GA transition, the novel 1032 GC transversion, and a
recent GT 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.
Key Words: long-QT syndrome • mutation • ion channels
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