© 1999 American Heart Association, Inc.
Original Contribution |
Genomic Organization of the KCNQ1 K+ Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome
From INSERM U153, Institut de Myologie (N.N., N.V., C.D., B.H., K.S., P.G.), Hôpital Pitié-Salpêtrière, Paris, France; Service de Biochimie B (P.R., L.D., B.H.), Hôpital Pitié-Salpêtrière, Paris, France; Service de Cardiologie (N.N., I.D., P.C.), Hôpital Lariboisière, Paris, France; Institute of Pediatry and Children Surgery (M.S.), Moscow, Russia; Falvaloro Foundation (R.P.), Buenos Aires, Argentina; and Service de Cardiologie (P.C.), Hôpital Louis Pradel, Lyon, France.
Correspondence to Nathalie Neyroud, INSERM U153, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75013 Paris, France. E-mail nneyroud{at}myologie.infobiogen.fr
Abstract—The voltage-gated
K+ channel KVLQT1 is essential for the
repolarization phase of the cardiac action potential and for
K+ homeostasis in the inner ear. Mutations in the human
KCNQ1 gene encoding the 
subunit of the KVLQT1
channel cause the long-QT syndrome (LQTS). The autosomal dominant form
of this cardiac disease, the Romano-Ward syndrome, is characterized by
a prolongation of the QT interval, ventricular
arrhythmias, and sudden death. The autosomal recessive form,
the Jervell and Lange-Nielsen syndrome, also includes bilateral
deafness. In the present study, we report the entire genomic
structure of KCNQ1, which consists of 19 exons spanning
400 kb on chromosome 11p15.5. We describe the sequences of exon-intron
boundaries and oligonucleotide primers that allow
polymerase chain reaction (PCR) amplification of exons from genomic
DNA. Two new (CA)n repeat microsatellites were found in
introns 10 and 14. The present study provides helpful tools for the
linkage analysis and mutation screening of the complete
KCNQ1 gene. By use of these tools, five novel mutations
were identified in LQTS patients by PCR–single-strand
conformational polymorphism (SSCP) analysis in the
C-terminal part of KCNQ1: two missense mutations, a
20-bp and 1-bp deletions, and a 1-bp insertion. Such mutations in the
C-terminal domain of the gene may be more frequent than previously
expected, because this region has not been analyzed so far.
This could explain the low percentage of mutations found in large
LQTS cohorts.
Key Words: KCNQ1 • KVLQT1 • K+ channel • long-QT syndrome
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