Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations

Hui Huang, Georg Kuenze, Jarrod A. Smith, Keenan C. Taylor, Amanda M. Duran, Arina Hadziselimovic, Jens Meiler, Carlos G. Vanoye, Alfred L. George, Charles R. Sanders*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments combined with channel functional data provided the basis for classifying each mutation into one of six mechanistic categories, highlighting heterogeneity in the mechanisms resulting in channel dysfunction or LOF. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the VSD, generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutationinduced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that five of the folding-defective LQTS mutant sites are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels.

Original languageEnglish (US)
Article numbereaar2631
JournalScience Advances
Volume4
Issue number3
DOIs
StatePublished - Mar 7 2018

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations'. Together they form a unique fingerprint.

Cite this