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Novel muscle chloride channel mutations and their effects on heterozygous carriers
V Mailänder1, R Heine, F Deymeer
1Department of Applied Physiology, University of Ulm, Germany.
Abstract:
Mutations within CLCN1, the gene encoding the major skeletal muscle chloride channel, cause either dominant Thomsen disease or recessive Becker-type myotonia, which are sometimes difficult to discriminate, because of reduced penetrance or lower clinical expressivity in females. We screened DNA of six unrelated Becker patients and found four novel CLCN1 mutations (Gln-74-Stop, Tyr-150-Cys, Tyr-261-Cys, and Ala-415-Val) and a previously reported 14-bp deletion. Five patients were homozygous for the changes (Gln-74-Stop, Ala-415-Val, and 14-bp deletion), four of them due to parental consanguinity. The sixth patient revealed compound heterozygosity for Tyr-150-Cys and Tyr-261-Cys. Heterozygous carriers of the Becker mutations did not display any clinical symptoms of myotonia. However, all heterozygous males, but none of the heterozygous females, exhibited myotonic discharges in the electromyogram suggesting (i) a gene dosage effect of the mutations on the chloride conductance and (ii) male predominance of subclinical myotonia. Furthermore, we report a novel Gly-200-Arg mutation resulting in a dominant phenotype in a male and a partially dominant phenotype in his mother. We discuss potential causes of the gender preference and the molecular mechanisms that may determine the mode of inheritance.
Insights
Mutations in the CLCN1 gene cause myotonia congenita. This study identifies novel mutations and reveals male predominance in subclinical myotonia, impacting disease diagnosis and inheritance understanding.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Mutations in the CLCN1 gene cause Thomsen disease (dominant) and Becker-type myotonia (recessive).
- Discriminating between these conditions can be challenging due to reduced penetrance and variable expressivity, particularly in females.
- The CLCN1 gene encodes the primary skeletal muscle chloride channel crucial for muscle relaxation.
Purpose of the Study:
- To identify novel mutations in the CLCN1 gene associated with myotonia congenita.
- To investigate the clinical and electrophysiological phenotypes of patients with identified CLCN1 mutations.
- To explore potential gender-specific effects on disease expression and inheritance patterns.
Main Methods:
- Screening of DNA from six unrelated Becker myotonia patients for CLCN1 mutations.
- Genetic analysis including sequencing to identify mutations.
- Electromyography (EMG) to detect myotonic discharges in patients and heterozygous carriers.
- Clinical assessment of affected individuals and their families.
Main Results:
- Four novel CLCN1 mutations (Gln-74-Stop, Tyr-150-Cys, Tyr-261-Cys, Ala-415-Val) and one previously reported deletion were identified in Becker patients.
- Five patients were homozygous for mutations, with four cases resulting from parental consanguinity.
- Heterozygous males showed subclinical myotonia (myotonic discharges on EMG), while heterozygous females did not, suggesting a gene dosage effect and male predominance.
- A novel dominant mutation (Gly-200-Arg) was identified, exhibiting a partially dominant phenotype in a mother.
Conclusions:
- Novel CLCN1 mutations contribute to recessive and dominant forms of myotonia congenita.
- Subclinical myotonia in heterozygous carriers demonstrates a potential gene dosage effect and a male predominance.
- Understanding these genetic variations and gender-specific effects is crucial for accurate diagnosis and genetic counseling in myotonia congenita.