(Circulation. 1999;99:1464-1470.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
C-terminal HERG Mutations
The Role of Hypokalemia and a KCNQ1-Associated Mutation in Cardiac Event Occurrence
From INSERM U153 (M.B., C.D., K.S., B.H., P.G.) and Service de Biochimie (L.D., P.R., B.H.), Groupe Hospitalier Pitié-Salpêtrière, Paris; Service de Cardiologie (I.D., P.C.), Hôpital Lariboisière, Paris, France; Centre Hospitalier des Ardennes (H.H.), site de Sainte-Ode, Belgium; Service de Cardiologie A (D.K.), CHU Lille, France; Institute for Arteriosclerosis Research (E.S.-B., H.F.), University of Münster, and Department of Cardiology (E.S.-B.), Hospital of the University of Münster, Germany.
Correspondence to Pascale Guicheney, INSERM U153, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France. E-mail pguichen{at}myologie.infobiogen.fr
Background—The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes KCNQ1 and HERG. In this study, we investigated the 3' part of HERG for mutations.
Methods and Results—New specific primers allowed the amplification of the 3' part of HERG, the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of HERG, 2592+1G-A, and a paternally inherited mutation, A341E, was identified in KCNQ1. The 2 more severely affected sisters bore both mutations.
Conclusions—The discovery of mutations in the C-terminal part of HERG emphasizes that this region plays a significant role in cardiac repolarization. Clinical data suggests that these mutations may be less malignant than mutations occurring in the pore region, but they can become clinically significant in cases of hypokalemia. The first description of 2 patients with double heterozygosity associated with a dramatic malignant phenotype implies that genetic analysis of severely affected young patients should include an investigation for >1 mutation in the LQT genes.
Key Words: long-QT syndrome • torsade de pointes • hypokalemia • LQT1 • LQT2
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