title: Myotonia congenita: novel mutations in CLCN1 gene and functional characterizations in Italian patients.
abstract: Myotonia congenita is an autosomal dominantly or recessively inherited muscle disorder causing impaired muscle relaxation and variable degrees of permanent muscle weakness, abnormal currents linked to the chloride channel gene (CLCN1) encoding the chloride channel on skeletal muscle membrane. We describe 12 novel mutations: c.1606G>C (p.Val536Leu), c.2533G>A (p.Gly845Ser), c.2434C>T (p.Gln812X), c.1499T>G (p.E500X), c.1012C>T (p.Arg338X), c.2403+1G>A, c.2840T>A (p.Val947Glu), c.1598C>T (p.Thr533Ile), c.1110delC, c.590T>A (p.Ile197Arg), c.2276insA Fs800X, c.490T>C (p.Trp164Arg) in 22 unrelated Italian patients. To further understand the functional outcome of selected missense mutations (p.Trp164Arg, p.Ile197Arg and p.Gly845Ser, and the previously reported p.Gly190Ser) we characterized the biophysical properties of mutant ion channels in tsA cell model. In the physiological range of muscle membrane potential, all the tested mutations, except p.Gly845Ser, reduced the open probability, increased the fast and slow components of deactivation and affected pore properties. This suggests a decrease in macroscopic chloride currents impairing membrane potential repolarization and causing hyperexcitability in muscle membranes. Detailed clinical features are given of the 8 patients characterized by cell electrophysiology. These data expand the spectrum of CLCN1 mutations and may contribute to genotype-phenotype correlations. Furthermore, we provide insights into the fine protein structure of ClC-1 and its physiological role in the maintenance of membrane resting potential.
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Gianna
authors.initials: G
authors.lastname: Ulzi
authors.forename: Marzia
authors.initials: M
authors.lastname: Lecchi
authors.forename: Valeria
authors.initials: V
authors.lastname: Sansone
authors.forename: Elisa
authors.initials: E
authors.lastname: Redaelli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Corti
authors.forename: Domenica
authors.initials: D
authors.lastname: Saccomanno
authors.forename: Serena
authors.initials: S
authors.lastname: Pagliarani
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Monika
authors.initials: M
authors.lastname: Raimondi
authors.forename: Grazia
authors.initials: G
authors.lastname: D'Angelo
authors.forename: Anna
authors.initials: A
authors.lastname: Modoni
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
authors.forename: Enzo
authors.initials: E
authors.lastname: Wanke
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lucchiari
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000473:pathology; D002648:Child; D018118:Chloride Channels / Q000235:genetics*; D004553:Electric Conductivity; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D009224:Myotonia Congenita / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D055815:Young Adult
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels