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Circulation. 1998 Jan 20;97(2):142-6.

Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome.

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  • 1Department of Cardiology, Children's Hospital, Harvard Medical School, Boston, Mass 02115, USA.



Long-QT syndrome (LQTS) is a disorder of ventricular repolarization characterized by a prolonged QT interval, syncope, seizures, and sudden death. Recently, three forms of LQTS have been shown to result from mutations in potassium or sodium ion channel genes: KVLQT1 for LQT1, HERG for LQT2, and SCN5A for LQT3. IsK, an apparent potassium channel subunit encoded by KCNE1 on chromosome 21, regulates both KVLQT1 and HERG. This relationship makes KCNE1 a likely candidate gene, because mutations of these genes are known to cause both the autosomal dominant Romano-Ward and recessive Jervell and Lange-Nielsen (JLN) forms of LQTS.


We screened 84 unrelated patients with Romano-Ward and 4 with JLN for possible mutations in KCNE1. We identified one homozygous mutation in a JLN patient that results in the nonconservative substitution of Asn for Asp at amino acid 76. The patient is congenitally deaf-mute, with recurrent syncopal events and a greatly prolonged QTc interval. The proband's mother and half-sister are both heterozygous for this mutation. Remarkably, both these family members have prolonged QTc intervals and would have been classified as Romano-Ward patients if not for the proband's diagnosis of JLN. This mutation was not identified in more than 100 control individuals.


These data provide strong evidence that KCNE1 mutations represent a fifth LQTS locus (LQT5). Further functional analysis, as well as the identification of more LQTS patients with KCNE1 mutations, will be important to confirm the role of IsK in LQTS.

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