Myotonia congenita: Novel mutations in CLCN1 gene and functional characterizations in Italian patients

Gianna Ulzi, Marzia Lecchi, Valeria Sansone, Elisa Redaelli, Eleonora Corti, Domenica Saccomanno, Serena Pagliarani, Stefania Corti, Francesca Magri, Monika Raimondi, Grazia D'Angelo, Anna Modoni, Nereo Bresolin, Giovanni Meola, Enzo Wanke, Giacomo P. Comi, Sabrina Lucchiari

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)65-71
Number of pages7
JournalJournal of the Neurological Sciences
Volume318
Issue number1-2
DOIs
Publication statusPublished - Jul 15 2012

Keywords

  • Becker's generalized myotonia
  • Channelopathy
  • CLCN1 gene
  • Myotonia congenita
  • Skeletal muscle
  • Thomsen's disease

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

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