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Mutations in the hminK gene cause long QT syndrome and suppress lKs function

Nature Genetics volume 17, pages 338340 (1997) | Download Citation

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Abstract

Ion-channel β-subunits are ancillary proteins that co-assemble with α-subunits to modulate the gating kinetics and enhance stability of multimeric channel complexes1,2. Despite their functional importance, dysfunction of potassium-channel p-subunits has not been associated with disease. Recent physiological studies suggest that KCNE1 encodes p-subunits (hminK) that co-assemble with KvLQTI a-subunits to form the slowly activating delayed rectifier K+ (lKs) channel3,4. Because KVLQTI mutations cause arrhythmia susceptibility in the long QT syndrome (LQT)5–7, we hypothesized that mutations in KCNE1 also cause this disorder. Here, we define KCNE1 missense mutations in affected members of two LQT families. Both mutations (S74L, D76N) reduced IKS by shifting the voltage dependence of activation and accelerating channel deactivation. D76N hminK also had a strong dominant-negative effect. The functional consequences of these mutations would be delayed cardiac repolarization and an increased risk of arrhythmia. This is the first description of KCNE1 as an LQT gene and confirms that hminK is an integral protein of the IKS channel.

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Author information

Affiliations

  1. Department of Human Genetics,University of Utah, Salt Lake City, Utah 84112, USA.

    • Igor Splawski
    •  & Mark T. Keating
  2. Department of Pediatrics,University of Utah, Salt Lake City, Utah 84112, USA.

    • Martin Tristani-Firouzi
    •  & Mark T. Keating
  3. Eccles Program in Human Molecular Biology and Genetics,University of Utah, Salt Lake City, Utah 84112, USA.

    • Michael C. Sanguinetti
  4. Department of Medicine and Division of Cardiology,University of Utah, Salt Lake City, Utah 84112, USA.

    • Michael C. Sanguinetti
    •  & Mark T. Keating
  5. Howard Hughes Medical Institute, University of Utah, Salt Lake City, Utah 84112, USA.

    • Mark T. Keating
  6. Arrhythmia Center, Sinai Hospital, Detroit, Michigan 48235, USA.

    • Michael H. Lehmann

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DOI

https://doi.org/10.1038/ng1197-338