Evolutionary analyses of KCNQ1 and HERG voltage-gated potassium channel sequences reveal location-specific susceptibility and augmented chemical severities of arrhythmogenic mutations
Mutations in HERG and KCNQ1 potassium channels are associated with Long QT syndrome and atrial fibrillation, and more recently to sudden infant death syndrome and sudden unexplained death. In proteins other than HERG and KCNQ1, disease-associated amino acid mutations have been analyzed according to the chemical severity of the change and the location of the altered amino acid according to its conservation over metazoan evolution.
Here, we present the first such analysis of arrhythmia-associated mutations (AAMs) in the HERG and KCNQ1 potassiumchannel genes.
Results: Using evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains.
Non-synonomous 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 also correlates with the proportion of a given amino acid associated with arrhythmias. At evolutionarily variable sites, the chemical severity of the changes is also correlated with the expected chemical severity of the involved codon.
Conclusions: Unlike 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 changes observed in evolution.
Author: Heather A Jackson and Eric A Accili
Credits/Source: BMC Evolutionary Biology 2008, 8:188
Published on: 2008-06-30
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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