MUTATION OF THE GENE FOR ISK ASSOCIATED WITH BOTH JERVELL AND LANGE-NIELSEN AND ROMANO-WARD FORMS OF LONG-QT SYNDROME

Background-Long-QT syndrome (LQTS) is a disorder of ventricular repola rization characterized by a prolonged QT interval, syncope, seizures, and sudden death. Recently, three forms of LQTS have been shown to res ult from mutations in potassium or sodium ion channel genes: KVLQT1 fo r LQT1, HERG for LQT2, and SCN5A for LQT3. IsK, an apparent potassium channel subunit encoded by KCNE1 on chromosome 21, regulates both KVLQ T1 and HERG. This relationship makes KCNE1 a likely candidate gene, be cause mutations of these genes are known to cause both the autosomal d ominant Romano-Ward and recessive Jervell and Lange-Nielsen (JLN) form s of LQTS. Methods and Results-We screened 84 unrelated patients with Romano-Ward and 4 with JLN for possible mutations in KCNE1. We identif ied one homozygous mutation in a JLN patient that results in the nonco nservative substitution of Asn for Asp at amino acid 76. The patient i s congenitally deaf-mute, with recurrent syncopal events and a greatly prolonged QT, interval. The proband's mother and half-sister are both heterozygous for this mutation. Remarkably, both these family members have prolonged QT, intervals and would have been classified as Romano -Ward patients if not for the proband's diagnosis of JLN. This mutatio n was not identified in more than 100 control individuals. Conclusions -These data provide strong evidence that KCNE1 mutations represent a f ifth LQTS locus (LQTS). Further functional analysis, as well as the id entification of more LQTS patients with KCNE1 mutations, will be impor tant to confirm the role of IsK in LQTS.