Brain, Vol. 125, No. 11, 2392-2407,
November 2002
© 2002 Oxford University Press
Novel CLCN1 mutations with unique clinical and electrophysiological consequences
1 Departments of Human Genetics, Molecular Genetics and Biochemistry and 2 Department of Neurology, University of Pittsburgh, PA, 3 Research Center for Genetic Medicine, Children’s National Medical Center, Washington, DC, 4 Transgenomic Inc., Gaithersburg, MD, 5 Department of Neurology, University of Colorado Health Sciences Center, Denver, CO, 6 Department of Neurology, University of Connecticut Health Center, Farmington, CT, 7 Department of Neurology, University of Maryland Hospital, Baltimore, MD, USA, 8 Department of General Physiology, University of Ulm, Ulm, 9 Institute of Physiology, RWTH Aachen, Aachen, Germany, 10 Department of Neurosciences, University of Turin, Italy and 11 Centro de Estudios Cientificos (CECS), Valdivia, ChileCorrespondence to: Dr Christoph Fahlke, Institute of Physiology, RWTH Aachen, Pauwelsstrasse 30, 52057, Aachen, Germany E-mail: chfahlke@physiology.rwth-aachen.de
Myotonia is a condition characterized by impaired relaxation of muscle following sudden forceful contraction. We systematically screened all 23 exons of the CLCN1 gene in 88 unrelated patients with myotonia and identified mutations in 14 patients. Six novel mutations were discovered: five were missense (S132C, L283F, T310M, F428S and T550M) found in heterozygous patients, and one was a nonsense mutation (E193X) in a homozygous patient. While five patients had a clinical diagnosis of myotonia congenita, the patient with the F428S mutation exhibited symptoms characteristic of paramyotonia congenita—a condition usually thought to be caused by mutations in the sodium channel gene SCN4A. Nevertheless, no mutations in SCN4A were identified in this patient. The functional consequences of the novel CLCN1 sequence variants were explored by recording chloride currents from human embryonic kidney cells transiently expressing homo- or heterodimeric mutant channels. The five tested mutations caused distinct functional alterations of the homodimeric human muscle chloride ion channel hClC-1. S132C and T550M conferred novel hyperpolarization-induced gating steps, L283F and T310M caused a shift of the activation curve to more positive potentials and F428S reduced the expression level of hClC-1 channels. All showed a dominant-negative effect. For S132C, L283F, T310M and T550M, heterodimeric channels consisting of one wild-type (WT) and one mutant subunit exhibited a shifted activation curve at low intracellular [Cl–]. WT-F428S channels displayed properties similar to WT hClC-1, but expressed at significantly lower levels. The novel mutations exhibit a broad variety of functional defects that, by distinct mechanisms, cause a significant reduction of the resting chloride conductance in muscle of heterozygous patients. Our results provide novel insights into functional alterations and clinical symptoms caused by mutations in CLCN1.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Bernard, C. Poulin, J. Puymirat, D. Sternberg, and M. Shevell Dosage Effect of a Dominant CLCN1 Mutation: A Novel Syndrome J Child Neurol, February 1, 2008; 23(2): 163 - 166. [Abstract] [PDF]
|
|
|
|
 |
|
 E. Rossignol, J. Mathieu, I. Thiffault, M. Tetreault, M. -J. Dicaire, N. Chrestian, N. Dupre, J. Puymirat, and B. Brais A novel founder SCN4A mutation causes painful cold-induced myotonia in French-Canadians Neurology, November 13, 2007; 69(20): 1937 - 1941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Tian, Y. Fu, D. H. Wang, and D. M. Cohen Regulation of TRPV1 by a novel renally expressed rat TRPV1 splice variant Am J Physiol Renal Physiol, January 1, 2006; 290(1): F117 - F126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T D Graves and M G Hanna Neurological channelopathies Postgrad. Med. J., January 1, 2005; 81(951): 20 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Berg, H. Jiang, C. A. Thornton, and S. C. Cannon Truncated ClC-1 mRNA in myotonic dystrophy exerts a dominant-negative effect on the Cl current Neurology, December 28, 2004; 63(12): 2371 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hebeisen, A. Biela, B. Giese, G. Muller-Newen, P. Hidalgo, and C. Fahlke The Role of the Carboxyl Terminus in ClC Chloride Channel Function J. Biol. Chem., March 26, 2004; 279(13): 13140 - 13147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Duffield, G. Rychkov, A. Bretag, and M. Roberts Involvement of Helices at the Dimer Interface in ClC-1 Common Gating J. Gen. Physiol., February 3, 2003; 121(2): 149 - 161. [Abstract] [Full Text] [PDF]
|
|