Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias

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Item Type:	Article
Title:	Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias
Creators Name:	Wollnik, B., Schroeder, B.C., Kubisch, C., Esperer, H.D., Wieacker, P. and Jentsch, T.J.
Abstract:	The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels. The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown. Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. Co-expression of KvLQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac Iks current. We now show that IsK not only changes the kinetics of KvLQT1 currents, but also its ion selectivity. Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant-negative mechanism. By contrast, a JLN mutation truncating the carboxyterminus of the KvLQT1 channel protein abolishes channel function without having a dominant-negative effect. This fully explains the different patterns of inheritance. Further, we identified a novel splice variant of the KVLQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.
Keywords:	Amino Acid Sequence, Base Sequence, Molecular Cloning, Complementary DNA, Dominant Genes, Recessive Genes, KCNQ1 Potassium Channel, Long QT Syndrome, Molecular Sequence Data, Mutation, Pedigree, Voltage-Gated Potassium Channels
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	6
Number:	11
Page Range:	1943-1949
Date:	October 1997
Official Publication:	http://hmg.oxfordjournals.org/cgi/content/abstract/6/11/1943
PubMed:	View item in PubMed

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