Evolutionary analyses of KCNQ1 and HERG voltage-gated potassium channel sequences reveal location-specific susceptibility and augmented chemical severities of arrhythmogenic mutations

Heather A Jackson,Eric A Accili

doi:10.1186/1471-2148-8-188

Abstract

BackgroundMutations in HERG and KCNQ1 potassium channels have been associated with Long QT syndrome and atrial fibrillation, and more recently with sudden infant death syndrome and sudden unexplained death. In other proteins, disease-associated amino acid mutations have been analyzed according to the chemical severity of the changes and the locations of the altered amino acids according to their conservation over metazoan evolution. Here, we present the first such analysis of arrhythmia-associated mutations (AAMs) in the HERG and KCNQ1 potassium channels.ResultsUsing evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains. Non-synonymous single nucleotide polymorphisms (nsSNPs) are under-represented at evolutionarily conserved sites in HERG, but distribute randomly in KCNQ1. AAMs are chemically more severe, according to Grantham's Scale, than changes observed in evolution and their severity correlates with the expected chemical severity of the involved codon. Expected chemical severity of a given amino acid also correlates with its relative contribution to arrhythmias. At evolutionarily variable sites, the chemical severity of the changes is also correlated with the expected chemical severity of the involved codon.ConclusionUnlike nsSNPs, AAMs preferentially locate to evolutionarily conserved, and functionally important, sites and regions within HERG and KCNQ1, and are chemically more severe than changes which occur in evolution. Expected chemical severity may contribute to the overrepresentation of certain residues in AAMs, as well as to evolutionary change.

Highlights

Mutations in HERG and KCNQ1 potassium channels have been associated with Long QT syndrome and atrial fibrillation, and more recently with sudden infant death syndrome and sudden unexplained death
Missense mutations that fell within the aligned region were used, and each was included only once, to eliminate frequency bias, but multiple disease mutations could be associated with a single site. Non-synonymous single nucleotide polymorphisms (nsSNPs) were collected from NCBI dbSNP, HAPMAP international and primary literature and were assumed to be phenotypically neutral based on their inclusion in the different databases. nsSNPs that overlapped with identified disease mutations were removed
The final data set used for HERG consists of 172 associated mutations (AAMs) at 134 sites and 16 nsSNPs at 16 individual sites

Summary

Introduction

Mutations in HERG and KCNQ1 potassium channels have been associated with Long QT syndrome and atrial fibrillation, and more recently with sudden infant death syndrome and sudden unexplained death. Mutations that disrupt normal biosynthesis and function of KCNQ1 and HERG have been associated with three cardiac arrhythmias: Short QT syndrome (SQTS) [5,6,7], atrial fibrillation [8,9] and Long QT syndrome (LQTS) [10,11]. BMC Evolutionary Biology 2008, 8:188 http://www.biomedcentral.com/1471-2148/8/188 mutations (AAMs) in each channel, with more than 95% of which are linked to LQTS This arrhythmia, which affects an estimated 1 in 5000–10000 people worldwide, is characterized by a prolongation of the QT interval on an electrocardiogram and can lead to Torsade de Pointes (TdP), ventricular fibrillation and sudden cardiac death [12,13]. Ninety percent of all known LQTS-associated mutations occur in HERG and KCNQ1

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