CLCN1 – Autosomal Dominant Myotonia Congenita

Autosomal dominant myotonia congenita (Thomsen disease) is a non-dystrophic skeletal muscle channelopathy characterized by impaired muscle relaxation after contraction, muscle stiffness, warm-up phenomenon, and percussion and hand-grip myotonia (HP:0003552). The disease is caused by heterozygous mutations in the CLCN1 gene encoding the skeletal muscle chloride channel ClC-1. ClC-1 maintains resting membrane potential via voltage-dependent chloride conductance; dominant mutations alter gating or exert dominant-negative effects, whereas recessive mutations typically cause loss-of-function.

Family studies have delineated dominant inheritance with incomplete penetrance. Four U.S. families (38 mutation-positive members) segregating the G230E variant demonstrated mild to subclinical myotonia and cold sensitivity, confirming a dominant-negative mechanism ([PMID:8857727]). In a consanguineous Arab pedigree, 12 of 24 relatives carried the G190S variant, with heterozygotes variably asymptomatic or mildly affected, and homozygotes severely myotonic ([PMID:19697366]). Segregation of 11 additional affected relatives supports strong familial linkage.

Over 200 CLCN1 variants are reported, predominantly autosomal dominant missense changes. A prototypical variant, c.697G>A (p.Gly233Ser), increases fast-gate open probability from ~0.4 to >0.9 at –90 mV, correlating with clinical muscle stiffness in a U.S. Thomsen family ([PMID:22790975]). The carboxyl-terminal frameshift c.2330del (p.Gly777fs), identified in a Swedish kindred, produces a truncated ClC-1 that causes dominantly inherited myotonia despite dual inheritance patterns ([PMID:16629771]). Other missense variants include c.1439C>A (p.Pro480His) associated with ptosis and reduced ClC-1 sarcolemmal expression ([PMID:27666773]).

Functional assays in Xenopus oocytes and mammalian cells confirm pathogenic gating defects. The G230E mutation alters anion selectivity and reverses rectification, indicating pore disruption ([PMID:9122265]). Exon 8 hotspot mutations cluster at the intersubunit interface and exert dominant-negative effects on common-gate function, consistent with a homotetrameric channel architecture ([PMID:17932099]). Trafficking studies reveal that A531V and F413C mutants are ER-retained or degraded, further reducing sarcolemmal ClC-1 conductance ([PMID:17990293]).

Collectively, genetic segregation in multiple pedigrees, case-control variant spectra, and concordant functional data establish a definitive CLCN1–autosomal dominant myotonia congenita association. This evidence underpins diagnostic CLCN1 sequencing, variant interpretation frameworks, and targeted electrophysiologic testing. Key Take-home: ClC-1 gating and trafficking defects from dominant CLCN1 mutations cause myotonia congenita and inform precision genetic counseling and personalized therapy.

References

• Acta neurologica Scandinavica • 2006 • Novel mutations at carboxyl terminus of CIC-1 channel in myotonia congenita. PMID:16629771
• Neurology • 1996 • Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect. PMID:8857727
• Muscle & Nerve • 2010 • Myotonia congenita in a large consanguineous Arab family: insight into the clinical spectrum of carriers and double heterozygotes of a novel mutation in the chloride channel CLCN1 gene. PMID:19697366
• Neuromolecular Medicine • 2012 • Dominantly inherited myotonia congenita resulting from a mutation that increases open probability of the muscle chloride channel CLC-1. PMID:22790975
• Proc Natl Acad Sci U S A • 1997 • A mutation in autosomal dominant myotonia congenita affects pore properties of the muscle chloride channel. PMID:9122265
• Brain • 2007 • Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions. PMID:17932099
• Muscle & Nerve • 2008 • F413C and A531V but not R894X myotonia congenita mutations cause defective endoplasmic reticulum export of the muscle-specific chloride channel CLC-1. PMID:17990293

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