Phenotype variation and newcomers in ion channel disorders.

D Bulman

doi:10.1093/hmg/6.10.1679

Abstract

Ion channels are part of a large family of macromolecules whose functions include the control and maintenance of electrical potential across cell membranes, secretion and signal transduction. Close inspection of the physiological processes involved in channel function and the secondary structure of various ion channels has served as a basis for subdividing ion channels into a number of superfamilies. The voltage-gated ion channels are one of these superfamilies. Recent work has shown that mutations in various ion channel genes are responsible for a number of neuromuscular and neurological disorders. Correlation of the various mutations with the clinical phenotype is providing us with insight into the pathophysiology of these channel proteins. Interestingly, different mutations within the same gene may cause quite distinct clinical disorders, while mutations in different channel genes may result in very similar phenotypes (genetic heterogeneity). Examples of phenotypic variation and genetic heterogeneity are presented in the context of the periodic paralytic disorders of skeletal muscle, episodic ataxia, migraine, long QT syndrome and paroxysmal dyskinesia. Some of these disorders are known to be caused by mutations in ion channel genes, while in the episodic movement disorders, ion channel genes are considered excellent candidate genes.

Highlights

The superfamily of voltage-gated K+, Na+ and Ca2+ channels are evolutionarily related, sharing a fundamental design consisting of a set of six potentially membrane spanning segments (S1–S6)
The periodic paralytic disorders of skeletal muscle and the non-dystrophic myotonias are diseases which are due to mutations in voltage-gated ion channel genes
Hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita, combined HyperPP and paramyotonia congenita, acetazolamide responsive myotonia and myotonia permanens/fluctuans are all clinically distinct autosomal dominant disorders which are due to mutations in the α-subunit of the skeletal muscle sodium channel, SCN4A [3,4,5,6,7,8] (Table 1, Fig. 1)

Summary

Phenotype variation and newcomers in ion channel disorders

Recent work has shown that mutations in various ion channel genes are responsible for a number of neuromuscular and neurological disorders. Different mutations within the same gene may cause quite distinct clinical disorders, while mutations in different channel genes may result in very similar phenotypes (genetic heterogeneity). Examples of phenotypic variation and genetic heterogeneity are presented in the context of the periodic paralytic disorders of skeletal muscle, episodic ataxia, migraine, long QT syndrome and paroxysmal dyskinesia. Some of these disorders are known to be caused by mutations in ion channel genes, while in the episodic movement disorders, ion channel genes are considered excellent candidate genes

INTRODUCTION

PERIODIC PARALYSIS

Amino acid mutation

EPISODIC ATAXIAS

LONG QT SYDNROME

PAROXYSMAL DYSKINESIA