title: A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene.
abstract: Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia) and caused by mutations in the chloride channel voltage-sensitive 1 (CLCN1) gene, encoding the voltage-gated chloride channel of skeletal muscle (ClC-1). In a large cohort of clinically diagnosed unrelated probands, we identified 75 different CLCN1 mutations in 106 individuals, among which 29 were novel mutations and 46 had already been reported. Despite the newly described mutations being scattered throughout the gene, in our patients, mutations were mostly found in exons 4 and 5. Most of the novel mutations located in the region comprising the intramembrane helices are involved in the ion-conducting pathway and predicted to affect channel function. We report for the first time that two mutations, inherited on the same allele as a heterozygous trait, abrogate disease expression, although when inherited singularly they were pathogenic. Such a mode of inheritance might explain the incomplete penetrance reported for autosomal dominant mutations in particular families.
authors.affiliation: Neurology IV-Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Brugnoni
authors.forename: Dimos
authors.initials: D
authors.lastname: Kapetis
authors.forename: Paola
authors.initials: P
authors.lastname: Imbrici
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
authors.forename: Eleonora
authors.initials: E
authors.lastname: Canioni
authors.forename: Lara
authors.initials: L
authors.lastname: Colleoni
authors.forename: Nicole Kerlero
authors.initials: NK
authors.lastname: de Rosbo
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Paola
authors.initials: P
authors.lastname: Cudia
authors.forename: Nasrin
authors.initials: N
authors.lastname: Gashemi
authors.forename: Pia
authors.initials: P
authors.lastname: Bernasconi
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Desaphy
authors.forename: Diana
authors.initials: D
authors.lastname: Conte
authors.forename: Renato
authors.initials: R
authors.lastname: Mantegazza
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009224:Myotonia Congenita / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels