In:
Journal of Cardiovascular Electrophysiology, Wiley, Vol. 19, No. 5 ( 2008-05), p. 541-549
Abstract:
Introduction: Slowly activating delayed‐rectifier potassium currents in the heart are produced by a complex protein with α and β subunits composed of the potassium voltage‐gated channel KQT‐like subfamily, member 1 (KCNQ1) and the potassium voltage‐gated channel Isk‐related family, member 1 (KCNE1), respectively. Mutations in KCNQ1 underlie the most common type of hereditary long QT syndrome (LQTS). Like other potassium channels, KCNQ1 has six transmembrane domains and a highly conserved potassium selectivity filter in the pore helix called “the signature sequence.” We aimed to investigate the functional consequences of a newly identified mutation within the signature sequence. Methods and Results: Potassium channel genomic DNA from a family with clinical evidence of LQTS was amplified by polymerase chain reaction (PCR), and the resulting products were then sequenced. Three family members had a double‐point mutation in KCNQ1 at nucleotides 938 (T‐to‐A) and 939 (C‐to‐A), resulting in an isoleucine‐to‐lysine change at amino acid position 313. These patients displayed prolonged QTc intervals (629, 508, and 500 ms 1/2, respectively) and repetitive episodes of syncope, but no deafness. Three‐dimensional structure modeling of KCNQ1 revealed that this mutation is located at the center of the channel pore. COS‐7 cells displayed a lack of current when transfected with a plasmid expressing the mutant. In addition, the mutant displayed a dominant negative effect on current but appeared normal with respect to plasma membrane integration. Conclusion: An I313K mutation within the selectivity filter of KCNQ1 results in a dominant‐negative loss of channel function, leading to a long QT interval and subsequent syncope.
Type of Medium:
Online Resource
ISSN:
1045-3873
,
1540-8167
DOI:
10.1111/jce.2008.19.issue-5
DOI:
10.1111/j.1540-8167.2007.01076.x
Language:
English
Publisher:
Wiley
Publication Date:
2008
detail.hit.zdb_id:
2037519-0
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