CLCN1 – Autosomal Recessive Myotonia Congenita

Autosomal recessive myotonia congenita (Becker disease) is caused by biallelic loss-of-function variants in the skeletal muscle chloride channel gene CLCN1 (Gene Symbol). Clinically, patients present with muscle stiffness (myotonia), warm-up phenomenon, and generalized hypertrophy (HP:0003720), often detectable as percussion myotonia (HP:0010548) and skeletal muscle hypertrophy (HP:0003712).

Genetic evidence supports an AR mode of inheritance with homozygous and compound heterozygous variants reported in 14 probands. Two siblings homozygous for c.1444G>C (p.Gly482Arg) exhibited myotonia and marked muscle hypertrophy in a Moroccan consanguineous family ([PMID:22346025]). An independent case harbored compound heterozygous c.1401+1G>A and c.1657A>T (p.Ile553Phe), confirming trans configuration in a Chinese patient ([PMID:30243293]). A series of 20 Italian patients included 11 with recessive myotonia and identified five novel recessive alleles (including missense, splice, nonsense, and frameshift) across unrelated families ([PMID:10215406]). Segregation of disease with biallelic variants in affected relatives in the consanguineous family further substantiates AR inheritance.

The variant spectrum includes missense (e.g., c.1444G>C (p.Gly482Arg) ([PMID:22346025])), splice‐site (c.1401+1G>A ([PMID:30243293])), frameshift (c.2203_2216del (p.Thr735ValfsTer57) ([PMID:38877370])) and nonsense changes (c.1024C>T (p.Arg338Ter) ([PMID:10215406])). Gly482Arg recurs in multiple ethnicities, underscoring its clinical relevance. Population carrier rates remain low, consistent with disease rarity.

Functional studies demonstrate that AR-associated CLCN1 variants abolish or severely reduce chloride currents. In vitro expression of nonsense and missense mutations in Xenopus oocytes and mammalian cells shows negligible currents and altered voltage dependence ([PMID:8112288]; [PMID:8119941]). The adr mouse model carries LoF Clc-1 alleles causing myotonia, mirroring human phenotype ([PMID:8119941]). Loss of ClC-1 reduces sarcolemmal chloride conductance, leading to muscle hyperexcitability.

No studies have refuted the AR association, and all functional assays align with a loss-of-function mechanism. The convergence of genetic and experimental data supports a robust gene–disease relationship.

Together, biallelic CLCN1 variants cause Becker myotonia via haploinsufficiency, confirmed by segregation and functional concordance. Genetic testing for CLCN1 informs diagnosis, guides management (e.g., mexiletine therapy), and enables family counseling.

Key Take-home: Biallelic loss-of-function CLCN1 variants cause autosomal recessive myotonia congenita; genetic confirmation underpins precision diagnosis and therapeutic decision-making.

References

• Annals of Indian Academy of Neurology • 2011 • Moroccan consanguineous family with Becker myotonia and review. PMID:22346025
• BMC Neurology • 2018 • A case report: autosomal recessive Myotonia congenita caused by a novel splice mutation (c.1401+1G>A) in CLCN1 gene of a Chinese Han patien PMID:30243293
• Human Mutation • 1998 • 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. PMID:10215406
• The Journal of Biological Chemistry • 1994 • Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice. PMID:8119941
• The EMBO Journal • 1994 • Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). PMID:8112288

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