Pathophysiological Role of Omega Pore Current in Channelopathies

In voltage-gated cation channels, a recurrent pattern for mutations is the neutralization of positively charged residues in the voltage-sensing S4 transmembrane segments. These mutations cause dominant ion channelopathies affecting many tissues such as brain, heart, and skeletal muscle. Recent studies suggest that the pathogenesis of associated phenotypes is not limited to alterations in the gating of the ion-conducting alpha pore. Instead, aberrant so-called omega currents, facilitated by the movement of mutated S4 segments, also appear to contribute to symptoms. Surprisingly, these omega currents conduct cations with varying ion selectivity and are activated in either a hyperpolarized or depolarized voltage range. This review gives an overview of voltage sensor channelopathies in general and focuses on pathogenesis of skeletal muscle S4 disorders for which current knowledge is most advanced

Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life

Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life

Genetic heterogeneity in hypokalemic periodic paralysis

Abstract Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases known to involve an abnormal function of ion channels. The latter includes hypokalemic and hyperkalemic periodic paralyses, and non-dystrophic myotonias. We recently showed genetic linkage of hypoPP to loci on chromosome lq31-32, co-localized with the DHP-sensitive calcium channel CACNL1A3. We propose to term this locus hypoPP-1. Using extended haplotypes with new markers located on chromosome lq31-32, we now report the detailed mapping of hypoPP-1 within a 7 cM interval. Two recombinants between hypoPP-1 and the flanking markers D1S413 and D1S510 should help to reduce further the hypoPP-1 interval. We used this new information to demonstrate that a large family of French origin displaying hypoPP is not genetically linked to hypoPP-1. We excluded genetic linkage over the entire hypoPP-1 interval showing for the first time genetic heterogeneity in hypoPE E. Plassart -A. Elbaz. J. V. Santos 9 J. Reboul 9 P. Lapie B. Fontaine ([5~) INSERM U134, H6pital de la Salp~tri6re

Muscle channelopathies and critical points in functional and genetic studies

Muscle channelopathies are caused by mutations in ion channel genes, by antibodies directed against ion channel proteins, or by changes of cell homeostasis leading to aberrant splicing of ion channel RNA or to disturbances of modification and localization of channel proteins. As ion channels constitute one of the only protein families that allow functional examination on the molecular level, expression studies of putative mutations have become standard in confirming that the mutations cause disease. Functional changes may not necessarily prove disease causality of a putative mutation but could be brought about by a polymorphism instead. These problems are addressed, and a more critical evaluation of the underlying genetic data is proposed