title: SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype.
abstract: In myotonic dystrophy type 2 (DM2), an association has been reported between early and severe myotonia and recessive chloride channel (CLCN1) mutations. No DM2 cases have been described with sodium channel gene (SCN4A) mutations. The aim is to describe a DM2 patient with severe and early onset myotonia and co-occurrence of a novel missense mutation in SNC4A. A 26-year-old patient complaining of hand cramps and difficulty relaxing her hands after activity was evaluated at our department. Neurophysiology and genetic analysis for DM1, DM2, CLCN1 and SCN4A mutations were performed. Genetic testing was positive for DM2 (2650 CCTG repeat) and for a variant c.215C>T (p.Pro72Leu) in the SCN4A gene. The variation affects the cytoplasmic N terminus domain of Nav1.4, where mutations have never been reported. The biophysical properties of the mutant Nav1.4 channels were evaluated by whole-cell voltage-clamp analysis of heterologously expressed mutant channel in tsA201 cells. Electrophysiological studies of the P72L variant showed a hyperpolarizing shift (-5 mV) of the voltage dependence of activation that may increase cell excitability. This case suggests that SCN4A mutations may enhance the myotonic phenotype of DM2 patients and should be screened for atypical cases with severe myotonia.
authors: Department of Biomedical Sciences for Health, IRCCS Policlinico San Donato, University of Milan, Italy.
authors: E
authors: E
authors: Bugiardini
authors: Department of Health Science, University of Milan Bicocca, Italy.
authors: I
authors: I
authors: Rivolta
authors: Department of Health Science, University of Milan Bicocca, Italy.
authors: A
authors: A
authors: Binda
authors: Department of Neurology, Penn State Hershey Medical Center, Hershey, PA, USA.
authors: A
authors: A
authors: Soriano Caminero
authors: Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Italy.
authors: F
authors: F
authors: Cirillo
authors: Department of Translational Surgeon and Medicine, University of Milan Bicocca, Italy.
authors: A
authors: A
authors: Cinti
authors: Department of Translational Surgeon and Medicine, University of Milan Bicocca, Italy.
authors: R
authors: R
authors: Giovannoni
authors: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy.
authors: A
authors: A
authors: Botta
authors: Laboratory of Muscle Histopathology and Molecular Biology, IRCCS Policlinico San Donato, Italy.
authors: R
authors: R
authors: Cardani
authors: Department of Neurology, Penn State Hershey Medical Center, Hershey, PA, USA.
authors: M P
authors: MP
authors: Wicklund
authors: Department of Biomedical Sciences for Health, IRCCS Policlinico San Donato, University of Milan, Italy; Laboratory of Muscle Histopathology and Molecular Biology, IRCCS Policlinico San Donato, Italy. Electronic address: giovanni.meola@unimi.it.
authors: G
authors: G
authors: Meola
mesh_terms: D000328:Adult; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics; D004252:DNA Mutational Analysis; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000503:physiopathology; D065636:Myotonin-Protein Kinase / Q000235:genetics; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016601:RNA-Binding Proteins / Q000235:genetics; D014162:Transfection
chemical_list: C086321:CLC-1 channel; C433227:CNBP protein, human; D018118:Chloride Channels; C585517:DMPK protein, human; D062553:NAV1.4 Voltage-Gated Sodium Channel; D016601:RNA-Binding Proteins; C106251:SCN4A protein, human; D065636:Myotonin-Protein Kinase
keywords: Myotonia; Myotonic dystrophy type 2; N-terminus; SCN4A