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

Jackson HA, Accili EA - BMC Evol. Biol. (2008)

Bottom Line: Using evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains.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 evolutionary change.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. hajacks@interchange.ubc.ca

ABSTRACT

Background: 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. 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.

Results: Using 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.

Conclusion: 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 evolutionary change.

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Arrhythmia-associated mutations are unevenly distributed among functionally conserved regions of HERG and KCNQ1 even after accounting for total length and evolutionary conservation of individual sites therein. a) Counts of observed number of AAMs per region (white), counts of expected number of AAMS based on a uniform distribution across each gene (black) and expected number of disease mutations based on an evolutionary distribution within each region (gray). Disease mutations are unevenly distributed among different regions of the channel: HERGuniform (X2(6 df) = 145.10, p < 0.001), HERGevolutionary (X2(6 df) = 116.55, p < 0.001), KCNQ1uniform (X2(5 df) = 81.59, p < 0.001) and KCNQ1evolutionary (X2(5 df) = 37.39, p < 0.001). b) Scatter plots showing the relationship between channel region conservation (average variability/site within domain) and the average number of observed disease mutations per site (diamonds) or expected number of disease mutations per site based on a uniform (circles) or evolutionary (triangles) distribution. Dotted and dashed lines indicate fits for expected uniform and evolutionary distribution, respectively. Solid lines represent best-fit regression of observed data. The correlation is significant for KCNQ1 but not for HERG, and the best fit of the KCNQ1 data is significantly different from the other two hypotheses.
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Figure 4: Arrhythmia-associated mutations are unevenly distributed among functionally conserved regions of HERG and KCNQ1 even after accounting for total length and evolutionary conservation of individual sites therein. a) Counts of observed number of AAMs per region (white), counts of expected number of AAMS based on a uniform distribution across each gene (black) and expected number of disease mutations based on an evolutionary distribution within each region (gray). Disease mutations are unevenly distributed among different regions of the channel: HERGuniform (X2(6 df) = 145.10, p < 0.001), HERGevolutionary (X2(6 df) = 116.55, p < 0.001), KCNQ1uniform (X2(5 df) = 81.59, p < 0.001) and KCNQ1evolutionary (X2(5 df) = 37.39, p < 0.001). b) Scatter plots showing the relationship between channel region conservation (average variability/site within domain) and the average number of observed disease mutations per site (diamonds) or expected number of disease mutations per site based on a uniform (circles) or evolutionary (triangles) distribution. Dotted and dashed lines indicate fits for expected uniform and evolutionary distribution, respectively. Solid lines represent best-fit regression of observed data. The correlation is significant for KCNQ1 but not for HERG, and the best fit of the KCNQ1 data is significantly different from the other two hypotheses.

Mentions: Because both channels possess functional regions that are well conserved among voltage-gated channels, we tested for uneven domain distribution of AAMs. KCNQ1 and HERG were divided into six or seven regions, respectively: N-terminus, PAS domain (HERG only), VSD (S1 through S4 transmembrane regions only), pore region (excluding outer turret), extracellular linkers, intracellular linkers and the C-terminus (see Figure 1). Based on the X2 analysis, AAMs in both channels are unevenly distributed among the defined functional domains and, in general, do not support either a uniform pattern (in which the number of randomly occurring mutations are proportional to the total number of residues) or evolutionary pattern (in which the number of randomly occurring mutations are proportional to the total number of conserved residues) (Figure 4a). For both channels, AAMs are overrepresented in the pore region. AAMs are found preferentially in the intracellular (IC) linker of KCNQ1 and the extracellular (EC) linker of HERG, as well as the PAS domain of HERG, but are underrepresented in the N- and C-termini of both channels. This finding is especially striking for KCNQ1 considering 32% of its disease mutations are found in the C-terminus. The number of AAMs in the VSD of HERG and KCNQ1 were not different from the expected number based on a uniform or evolutionary distribution.


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

Jackson HA, Accili EA - BMC Evol. Biol. (2008)

Arrhythmia-associated mutations are unevenly distributed among functionally conserved regions of HERG and KCNQ1 even after accounting for total length and evolutionary conservation of individual sites therein. a) Counts of observed number of AAMs per region (white), counts of expected number of AAMS based on a uniform distribution across each gene (black) and expected number of disease mutations based on an evolutionary distribution within each region (gray). Disease mutations are unevenly distributed among different regions of the channel: HERGuniform (X2(6 df) = 145.10, p < 0.001), HERGevolutionary (X2(6 df) = 116.55, p < 0.001), KCNQ1uniform (X2(5 df) = 81.59, p < 0.001) and KCNQ1evolutionary (X2(5 df) = 37.39, p < 0.001). b) Scatter plots showing the relationship between channel region conservation (average variability/site within domain) and the average number of observed disease mutations per site (diamonds) or expected number of disease mutations per site based on a uniform (circles) or evolutionary (triangles) distribution. Dotted and dashed lines indicate fits for expected uniform and evolutionary distribution, respectively. Solid lines represent best-fit regression of observed data. The correlation is significant for KCNQ1 but not for HERG, and the best fit of the KCNQ1 data is significantly different from the other two hypotheses.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Arrhythmia-associated mutations are unevenly distributed among functionally conserved regions of HERG and KCNQ1 even after accounting for total length and evolutionary conservation of individual sites therein. a) Counts of observed number of AAMs per region (white), counts of expected number of AAMS based on a uniform distribution across each gene (black) and expected number of disease mutations based on an evolutionary distribution within each region (gray). Disease mutations are unevenly distributed among different regions of the channel: HERGuniform (X2(6 df) = 145.10, p < 0.001), HERGevolutionary (X2(6 df) = 116.55, p < 0.001), KCNQ1uniform (X2(5 df) = 81.59, p < 0.001) and KCNQ1evolutionary (X2(5 df) = 37.39, p < 0.001). b) Scatter plots showing the relationship between channel region conservation (average variability/site within domain) and the average number of observed disease mutations per site (diamonds) or expected number of disease mutations per site based on a uniform (circles) or evolutionary (triangles) distribution. Dotted and dashed lines indicate fits for expected uniform and evolutionary distribution, respectively. Solid lines represent best-fit regression of observed data. The correlation is significant for KCNQ1 but not for HERG, and the best fit of the KCNQ1 data is significantly different from the other two hypotheses.
Mentions: Because both channels possess functional regions that are well conserved among voltage-gated channels, we tested for uneven domain distribution of AAMs. KCNQ1 and HERG were divided into six or seven regions, respectively: N-terminus, PAS domain (HERG only), VSD (S1 through S4 transmembrane regions only), pore region (excluding outer turret), extracellular linkers, intracellular linkers and the C-terminus (see Figure 1). Based on the X2 analysis, AAMs in both channels are unevenly distributed among the defined functional domains and, in general, do not support either a uniform pattern (in which the number of randomly occurring mutations are proportional to the total number of residues) or evolutionary pattern (in which the number of randomly occurring mutations are proportional to the total number of conserved residues) (Figure 4a). For both channels, AAMs are overrepresented in the pore region. AAMs are found preferentially in the intracellular (IC) linker of KCNQ1 and the extracellular (EC) linker of HERG, as well as the PAS domain of HERG, but are underrepresented in the N- and C-termini of both channels. This finding is especially striking for KCNQ1 considering 32% of its disease mutations are found in the C-terminus. The number of AAMs in the VSD of HERG and KCNQ1 were not different from the expected number based on a uniform or evolutionary distribution.

Bottom Line: Using evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains.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 evolutionary change.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. hajacks@interchange.ubc.ca

ABSTRACT

Background: 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. 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.

Results: Using 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.

Conclusion: 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 evolutionary change.

Show MeSH
Related in: MedlinePlus