ClC-1 chloride channel and myotonia in proximal myotonic myopathy
LicenseStandard (Fassung vom 03.05.2003)
Proximal myotonic myopathy (PROMM) is an autosomal dominant disorder caused by an untranslated CCTG repeat expansion in intron 1 of the zinc finger 9 gene (ZNF9) on chromosome 3. A predominate and early symptom of myotonic dystrophy is myotonia, manifested as delayed skeletal muscle relaxation following voluntary contraction. Myotonia can be caused by a loss of function of the muscle specific chloride channel (ClC-1). In muscle from patients with PROMM we identified a shorter variant of ClC-1-mRNA with exons 6 and 7 spliced out. This splicing variant contains a premature termination codon at position 236 that prevents expression of full length ClC-1 protein. Heterologous expression does not yield functional channels. Expression of CCTG-repeats in C2C12 cells reproduces the aberrant splicing of ClC-1 observed in PROMM skeletal muscle. This disruption in alternative splicing regulation of ClC-1 directly correlates with myotonia, a cardinal symptom of myotonic dystrophy.
Subject HeadingsMyotonie [GND]
RNA splicing [LCSH]
Myotonic diseases [MeSH]