title: A novel Ile1455Thr variant in the skeletal muscle sodium channel alpha-subunit in a patient with a severe adult-onset proximal myopathy with electrical myotonia and a patient with mild paramyotonia phenotype.
abstract: In sodium channelopathies, a severe fixed myopathy caused by a dominant mutation is rare. We describe two unrelated patients with a novel variant, p.Ile1455Thr, with phenotypes of paramyotonia in one case and fixed proximal myopathy with latent myotonia in another. In-vitro whole cell patch-clamp studies show that the mutation slows inactivation and accelerates recovery, in line with other paramyotonia variants with destabilized fast inactivation as pathomechanism. Additionally, p.IleI1455 causes a loss-of-function by reduced membrane insertion, right-shift of activation, and slowed kinetics. Molecular dynamics simulations comparing wild type and mutant Nav1.4 showed that threonine substitution hindered D4S4 mobility in response to membrane depolarization, consistent with effects of the mutation on channel inactivation. The fixed myopathy is likely to be associated to gain-of-function leading to sodium accumulation, regional edema, T-tubular swelling and mitochondrial stress. A possible contribution of the loss-of-function features towards myotonia and myopathy is discussed.
authors.affiliation: Division of Neurophysiology, Ulm University, Ulm, Germany.
authors.forename: Marcin
authors.initials: M
authors.lastname: Bednarz
authors.affiliation: Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bas C
authors.initials: BC
authors.lastname: Stunnenberg
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Benno
authors.initials: B
authors.lastname: Kusters
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.affiliation: Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Christiaan G
authors.initials: CG
authors.lastname: Saris
authors.affiliation: Department of Biological Sciences, Idaho State University, Pocatello, ID 83209, USA.
authors.forename: James
authors.initials: J
authors.lastname: Groome
authors.affiliation: Department of Biological Sciences, Idaho State University, Pocatello, ID 83209, USA.
authors.forename: Vern
authors.initials: V
authors.lastname: Winston
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, IRCCS Policlinico San Donato, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
authors.affiliation: Division of Neurophysiology, Ulm University, Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
authors.affiliation: Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Nicol.Voermans@Radboudumc.nl.
authors.forename: Nicol C
authors.initials: NC
authors.lastname: Voermans
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009224:Myotonia Congenita / Q000235:genetics* / Q000503:physiopathology*; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000503:physiopathology*; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human
keywords: Myopathy; Na(V)1.4 voltage-gated sodium channel; Paramyotonia congenita; Whole-cell recording