The CLCN1 gene encodes the votage gated skeletal muscle chloride channel, ClC-1. Mutations in CLCN1 cause Myotonia Congenita.

Disease relevance of CLCN1

• Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl- channel gene (CLCN1, 7q35) [1].
• In another family previously diagnosed as having Thomsen's disease, we unexpectedly found a CLCN1 14 bp deletion known to cause recessive myotonia, and a rare Trp-118-Gly polymorphism [2].
• Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel (CLCN1) gene, and the muscle sodium channel (SCN4A) gene, was assessed and excluded [3].
• Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing [4].
• The cause of several familial muscular diseases have recently been linked to mutations within skeletal muscle sodium and chloride channel genes [5].
• These findings are now consistent with, and provide a molecular explanation for, acidosis opposing fatigue by decreasing the chloride conductance of skeletal muscle via inhibition of ClC-1 [6].

High impact information on CLCN1

Chemical compound and disease context of CLCN1

• Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen) [7]
• A point mutation (D136G) predicting the substitution of glycine for aspartate in position 136 of the human muscle Cl- channel (hClC-1) causes recessive generalized myotonia [8] .

Biological context of CLCN1

• Recently, these two phenotypes have been associated with mutations in the major muscle chloride channel gene CLCN1 on human chromosome 7q35 [9].
• 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 [10].
• We have systematically screened the open reading frame of the CLCN1 gene for mutations by SSC analysis (SSCA) in a panel of 24 families and 17 single unrelated patients with human myotonia [9].
• Dominant myotonia congenita (Thomsen's disease) is linked to CLCN1, the gene encoding the major muscle chloride channel, localized on chromosome 7q35 [2].
• We now show that the protein-coding sequence of the CLCN1 gene is organized into 23 exons [11].

Anatomical context of CLCN1

• Current understanding does not include a molecular identification of most of the observed channel functions, but details of the molecular properties of these channel molecules should allow future identification and further understanding of chloride channel function in hepatocytes [12].
• Expression of CLCN voltage-gated chloride channel genes in human blood vessels [13].
• Differential expression of the human chloride channel genes in the trabecular meshwork under stress conditions [14] .

Associations of CLCN1 with chemical compounds

• 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 [15].
• This glycine residue is conserved in all known members of this class of chloride channel proteins [16].
• An unusual restriction site in the CLC-1 locus in two GM families identified a mutation associated with that disease, a phenylalanine-to-cysteine substitution in putative transmembrane domain D8 [17].
• Voltage-dependent blocks by intracellular and extracellular iodide help to distinguish two distinct ion binding sites within the hClC-1 conduction pathway [1].
• These findings suggest that Gly 230 is critical for normal ion conductance in hClC-1 and that this residue resides within the channel pore [1].

Physical interactions of CLCN1

• Conservation of chloride channel structure revealed by an inhibitor binding site in ClC-1 [18].
• The chloride channel and drug transport activities of P-glycoprotein appear to reflect two distinct functional states of the protein that can be interconverted by changes in tonicity [19].

Regulatory relationships of CLCN1

• A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity [20].
• Human ClC-3 is not the swelling-activated chloride channel involved in cell volume regulation [21].
• CIC-2 is a voltage- and volume-regulated chloride channel expressed in many tissues [22].
• We speculate that the NEG2 region interacts with other cytosolic domains of CFTR to control opening and closing transitions of the chloride channel [23].
• Recently, the calcium-activated chloride channel hCLCA1 has been described to be upregulated by IL-9 and has been thought to regulate the expression of soluble gel-forming mucins [24].

Other interactions of CLCN1

• An expansion in the ZNF9 gene causes PROMM in a previously described family with an incidental CLCN1 mutation [25].
• The family was not sufficiently informative to exclude linkage to the sodium channel gene SCN4A or the chloride channel gene CLC1 [26].
• The GM locus was again completely linked to both the CLCN1 and the TCRB gene in all families with a combined lod score of Z = 9.26 at a recombination fraction of theta = 0.00 [27].
• These findings suggest that RPE 28 SV4 cells possess regulated chloride channels including CFTR and members of the ClC chloride channel family [28] .

Analytical, diagnostic and therapeutic context of CLCN1

• The diagnosis of Myotonia Congenita is confirmed by identifying one or more causative mutations in the CLCN1 gene. However, not all sequence variants in CLCN1 are pathogenic. Classification of a CLCN1 sequence variants as pathogenic or benign is not always straightforward. Guidelines for the classification of sequence variants (in any gene) have been issued by the Clinical Molecular Genetics Society ( 
• A large proportion of CLCN1 mutations are point mutations, and the effect of these on the function of the ClC-1 protein can be studied by voltage clamp. Sequence variants that impair ClC-1 function are likely to be pathogenic.
• The authors used a mammalian cell (human embryonic kidney 293) expression system and the whole-cell voltage-clamp technique to functionally express and physiologically characterize five CLCN1 mutations [29].
• All 23 exons of the CLCN1 gene were analysed by direct sequencing of PCR products to detect the nucleotide changes [30].
• By means of two microelectrode voltage clamp recordings, we found that S(-)-CPP shifted the activation curve of the ClC-1 currents toward more positive potentials and decreased the residual conductance at negative membrane potential; both effects probably account for the decrease of gCl at resting potential of native muscle fibers [31].
• Skeletal muscle CLC-1 mRNA levels were decreased by denervation [32].
• Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele [33].

Links to sites describing CLCN1 and Myotonia Congenita

• NCBI gene review:  
• Leiden Open Variation Database CLCN1 page:  
• cDNA reference sequence for CLCN1:    

References