Non-Silent Story on Synonymous Sites in Voltage-Gated Ion Channel Genes

Tong Zhou,Eun A Ko,Wanjun Gu,Hyoweon Bang,Jae-Hong Ko,Inja Lim,Vladimir N Uversky

doi:10.1371/journal.pone.0048541

Abstract

Synonymous mutations are usually referred to as “silent”, but increasing evidence shows that they are not neutral in a wide range of organisms. We looked into the relationship between synonymous codon usage bias and residue importance of voltage-gated ion channel proteins in mice, rats, and humans. We tested whether translationally optimal codons are associated with transmembrane or channel-forming regions, i.e., the sites that are particularly likely to be involved in the closing and opening of an ion channel. Our hypothesis is that translationally optimal codons are preferred at the sites within transmembrane domains or channel-forming regions in voltage-gated ion channel genes to avoid mistranslation-induced protein misfolding or loss-of-function. Using the Mantel-Haenszel procedure, which applies to categorical data, we found that translationally optimal codons are more likely to be used at transmembrane residues and the residues involved in channel-forming. We also found that the conservation level at synonymous sites in the transmembrane region is significantly higher than that in the non-transmembrane region. This study provides evidence that synonymous sites in voltage-gated ion channel genes are not neutral. Silent mutations at channel-related sites may lead to dysfunction of the ion channel.

Highlights

Ion channels are membrane protein complexes that help establish and control the voltage gradient across biological membranes by allowing the flow of ions down their electrochemical gradient
Even a single-site mutation in these regions may lead to a change in channel conductance, voltage dependence, or activity level [6], which suggests that the nonsynonymous sites in transmembrane domains of voltage-gated ion channel genes are under stronger purifying selection than the sites in other regions in the same genes [13]
Optimal Codons are Preferred at Transmembrane Sites We first assessed whether there was any relationship between a codon’s translational optimality and the same codon’s tendency to be preferentially used at transmembrane sites in voltage-gate ion channel genes

Summary

Introduction

Ion channels are membrane protein complexes that help establish and control the voltage gradient across biological membranes by allowing the flow of ions down their electrochemical gradient. The ion channel conformational change between the closed and open states is called gating. Ion channels can be classified by gating, such as the chemical or physical modulator that controls their opening or closing activity. Voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane. It has been found that the amino acid sequences involved in pore-forming are highly conserved in voltage-gated ion channel proteins [10,11,12]. Even a single-site mutation in these regions may lead to a change in channel conductance, voltage dependence, or activity level [6], which suggests that the nonsynonymous sites in transmembrane domains of voltage-gated ion channel genes are under stronger purifying selection than the sites in other regions in the same genes [13]. The effect of synonymous mutations in voltage-gated ion channel genes is still unknown

Methods

Results

Conclusion