𝔖 Bobbio Scriptorium
✦   LIBER   ✦

Characterization of two new dominant ClC-1 channel mutations associated with myotonia

✍ Scribed by Morten Grunnet; Thomas Jespersen; Eskild Colding-Jørgensen; Marianne Schwartz; Dan A. Klaerke; John Vissing; Søren-Peter Olesen; Morten Dunø

Publisher
John Wiley and Sons
Year
2003
Tongue
English
Weight
393 KB
Volume
28
Category
Article
ISSN
0148-639X

No coin nor oath required. For personal study only.

✦ Synopsis

Abstract

Voltage‐gated ClC‐1 chloride channels encoded by the CLCN1 gene have a major role in setting the membrane potential in skeletal muscle. More than 60 CLCN1 mutations have been associated with myotonia congenita. These mutations are traditionally classified as recessive (Becker's disease) or dominant (Thomsen's disease). In this study, we have electrophysiologically characterized two new dominant ClC‐1 mutations, thereby elucidating the observed phenotype in patients. The two ClC‐1 mutants M128V and E193K were identified, and the DNA was isolated from patients and subsequently expressed in Xenopus laevis oocytes for electrophysiological characterization. Both ClC‐1 mutants, M128V and E193K, showed a large rightward shift in the current–voltage relationship. In addition, the activation kinetics were slowed in the ClC‐1 M128V mutant, as compared to the wild‐type ClC‐1. Interestingly, ClC‐1 E193K revealed a change in reversal potential compared to wild‐type channels. This finding supports the notion that the E193 amino acid is an important determinant in the selectivity filter of the human ClC‐1 channel. The electrophysiological behavior of both mutants demonstrates a severe reduction in ClC‐1 channel conductance under physiologically relevant membrane potentials. These studies thereby explain the molecular background for the observed myotonia in patients. Muscle Nerve 28: 722–732, 2003

📜 SIMILAR VOLUMES

Characterization of three myotonia-assoc
Characterization of three myotonia-associated mutations of the CLCN1 chloride channel gene via heterologous expression
✍ Bronwyn J. Simpson; Tamara A. Height; Grigori Y. Rychkov; Kristen J. Nowak; Nige 📂 Article 📅 2004 🏛 John Wiley and Sons 🌐 English ⚖ 190 KB

Two novel mutations of the human CLCN1 chloride channel gene, c.592C>G (p.L198V) and c.2255A>G (p.K752R), are described, occurring coincidentally in the one myotonic patient. These individual mutations and a construct with both mutations in the one cDNA were transcribed and expressed in Xenopus oocy

Identification of five new mutations and
Identification of five new mutations and three novel polymorphisms in the muscle chloride channel gene (CLCN1) in 20 Italian patients with dominant and recessive myotonia congenita
✍ F Sangiuolo; A Botta; A Mesoraca; S Servidei; L Merlini; G Fratta; G Novelli; B 📂 Article 📅 1998 🏛 John Wiley and Sons 🌐 English ⚖ 143 KB 👁 2 views

Autosomal dominant myotonia congenita or Thomsen's disease (OMIM\* 160800) and autosomal recessive myotonia congenita or Becker's (OMIM\* 255700) are rare nondystrophic disorders due to allelic mutations of the muscle chloride channel gene, CLCN1. We have analysed all 24 exons of the CLCN1 gene, in