Alternative titles; symbols
HGNC Approved Gene Symbol: CLCN1
SNOMEDCT: 20305008, 57938005, 726051002, 8960007; ICD10CM: G71.12;
Cytogenetic location: 7q34 Genomic coordinates (GRCh38): 7:143,316,111-143,352,083 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q34 | Myotonia congenita, dominant | 160800 | Autosomal dominant | 3 |
| Myotonia congenita, recessive | 255700 | Autosomal recessive | 3 | |
| Myotonia levior | 160800 | Autosomal dominant | 3 |
The muscle chloride channel CLCN1 regulates the electric excitability of the skeletal muscle membrane. Skeletal muscle has an unusually high resting Cl(-) conductance and in vitro studies suggest that reduction of this conductance causes electrical instability and resulting myotonia in both humans and animal models. Muscle Cl(-) conductance is predominantly mediated by the CLCN1 chloride channel (summary by Steinmeyer et al., 1994).
By homology screening with the major rat skeletal muscle chloride channel CLCN1, Koch et al. (1992) cloned a partial human CLCN1 cDNA that covered about 80% of the coding sequence. This region was 88% identical to the rat channel in amino acid sequence.
Chen et al. (2013) found expression of the CLCN1 gene in various human brain regions, including cerebellum, hippocampus, spinal cord, and cerebral cortex, as well as in heart. Clcn1 was also expressed in the brain and heart of developing and adult mice. In mouse brain, neuronal expression of Clcn1 was detected in the pyramidal and dentate granule cells of the hippocampus, cerebellar Purkinje cells, scattered brainstem nuclei, frontal neocortex, and thalamus. The results suggested that CLCN1 has a role in neuronal function and excitability in addition to its known role in skeletal muscle.
Steinmeyer et al. (1994) determined that CLCN1 functions as a homooligomer, most likely with 4 subunits.
Pusch et al. (1995) used a Xenopus transfection to demonstrate shifting of the gating of CLCN1 toward positive voltages by 4 different mutations identified in patients with myotonia congenita (160800). When these mutant cDNAs were coexpressed with wildtype subunits, they imposed altered voltage dependence on the heteromeric channels which would then open only in a voltage range where they could not contribute significantly to the repolarization of action potentials. Without such repolarizations, sodium channels have enough time to recover from inactivation leading to typical myotonic runs, which are a series of repetitive action potentials.
Cryoelectron Microscopy
Mindell et al. (2001) reported the formation of 2-dimensional crystals of the prokaryotic CLC channel homolog EriC reconstituted into phospholipid bilayer membranes. Cryoelectron microscopic analysis of these crystals yielded a projection structure at 6.5-angstrom resolution that showed off-axis water-filled pores within the dimeric channel complex.
Crystal Structure
Dutzler et al. (2002) presented the x-ray structures of 2 prokaryotic CLC chloride channels, from Salmonella typhimurium and E. coli, at 3.0 and 3.5 angstroms, respectively. Both structures revealed 2 identical pores, each pore being formed by a separate subunit contained within a homodimeric membrane protein.
Using the 3-dimensional crystal structure of a bacterial CLC protein to predict residues involved in chloride channel inhibitor binding, Estevez et al. (2003) identified an inhibitor-binding site in human CLCN1. The binding site is localized close to the chloride-binding site and is accessible only from the intracellular side. Estevez et al. (2003) concluded that the structures of bacterial CLCs can be extrapolated with fidelity to mammalian chloride channels.
Lorenz et al. (1994) showed that the protein coding sequence of the CLCN1 gene is organized into 23 exons. Its upstream region contains a canonical TATA box, several consensus binding sites for myogenic transcription factors, and 2 other putative regulatory elements.
By blot hybridization to a panel of chromosome 7-specific, human-mouse somatic cell hybrids, Koch et al. (1992) mapped the CLCN1 gene to 7q32-qter. With RFLPs in the CLCN1 gene, they demonstrated that the locus is linked to the T-cell receptor beta locus (see 186930) at 7q35 (maximum lod = 5.23 at theta = 0.0). In the mouse, it had previously been demonstrated that the corresponding loci are linked on chromosome 6, which shows other evidence of homology of synteny to human 7q (Steinmeyer et al., 1991).
Myotonia Congenita
In 3 brothers, born of consanguineous parents, with autosomal recessive myotonia congenita (Becker disease; 255700), Koch et al. (1992) identified a homozygous mutation in the CLCN1 gene (F413C; 118425.0001). In affected members of 3 unrelated families with autosomal dominant myotonia congenita (Thomsen disease; 160800), George et al. (1993) identified a heterozygous mutation in the CLCN1 gene (G230E; 118425.0002). The findings indicated that the 2 disorders are allelic.
Meyer-Kleine et al. (1995) identified 15 different mutations in the CLCN1 gene, of which 10 were novel, in a total of 17 unrelated families and 13 single patients with Becker-type myotonia congenita. One additional family had the dominant Thomsen form. Three mutations accounted for 32% of the Becker chromosomes in the German population; F413C, R894X (118425.0015), and a 14-bp deletion in exon 13 (118425.0009). Although a 437A-T transversion had been described as a disease-causing mutation (Koty et al., 1994), Meyer-Kleine et al. (1995) observed it in 3 myotonia families and in 5 of 200 control chromosomes, consistent with a polymorphism. Moreover, mutant 437A-T cRNA was functionally expressed in Xenopus oocytes and found to induce currents that were indistinguishable from wildtype currents.
In a screening of 6 unrelated patients with recessive Becker-type myotonia, Mailander et al. (1996) identified 4 novel CLCN1 mutations and a previously reported 14-bp deletion. Five patients were homozygous and the sixth patient was compound heterozygous. Heterozygous carriers of the Becker mutation did not display any clinical symptoms of myotonia; however, all heterozygous males, but none of the heterozygous females, exhibited myotonic discharges on EMG, suggesting a gene-dosage effect of the mutations on chloride conductance and a male predominance of subclinical myotonia.
Wollnik et al. (1997) analyzed the effect of 1 dominant and 3 recessive mutations in the CLCN1 gene after functional expression in Xenopus oocytes.
Esteban et al. (1998) stated that 31 specific mutations in the CLCN1 gene had been related to myotonia congenita in humans and 3 in mice. They described a homozygous arg317-to-gln (R317Q; 118425.0011) mutation in affected members of a family with autosomal recessive myotonia congenita. A heterozygous brother had mild muscle stiffness consistent with latent myotonia. The parents were unaffected, although only the mother, who was heterozygous, was available for DNA study. The same R317Q mutation had previously been identified in a family with dominant Thomsen myotonia congenita. At least 2 other mutations, G230E (118425.0002) and R894X, had been found in both dominant and recessive myotonia congenita, depending on the particular family.
Kubisch et al. (1998) identified 4 novel missense mutations in the CLCN gene, 2 in the dominant form and 2 in the recessive form of myotonia. The first 2 displayed a classic dominant phenotype with a dominant-negative effect by significantly imparting a voltage shift on mutant/wildtype heteromeric channels as found in heterozygous patients. One of the recessive mutations also shifted the voltage dependence to positive values, but coexpression with wildtype CLCN1 gave almost wildtype currents. The voltage dependence of mutant heteromeric channels was not always intermediate between those of the constituent homomeric channel subunits. These complex interactions correlated clinically with various inheritance patterns, ranging from autosomal dominant with various degrees of penetrance to autosomal recessive.
In affected members of 18 unrelated families from Norway and Sweden with both autosomal dominant (5 families) and autosomal recessive (13 families) inheritance of myotonia congenita, Sun et al. (2001) identified 8 different mutations (1 nonsense, 4 missense, and 3 splice mutations) in the CLCN1 gene; 3 mutations were novel. Fifteen patients had mutations on both alleles, consistent with the recessive disorder; 2 probands had mutations in a single allele; and 2 probands had no CLCN1 mutations. In 2 families, 3 CLCN1 mutations were found in the proband, and Sun et al. (2001) suspected that this phenomenon may be underestimated because mutation search in a disease gene usually ends by the identification of 2 mutations in a family with recessive inheritance. Families with apparently dominant segregation of myotonia congenita may actually represent recessive inheritance with undetected heterozygous individuals married-in as a consequence of a high population carrier frequency of some mutations. The findings, together with the very variable clinical presentation, challenged the classification into dominant Thomsen or recessive Becker disease. Sun et al. (2001) suggested that most cases of myotonia congenita show recessive inheritance with some modifying factors or genetic heterogeneity.
In a review, Pusch (2002) stated that more than 60 CLCN1 mutations had been identified as causing myotonia, with only a few of them being dominant. A dominant-negative effect of mutant subunits in mutant-wildtype heterodimers was suggested as the usual mechanism for dominant mutations.
Duno et al. (2004) reported 4 unrelated families with myotonia congenita and the R894X mutation: 2 families had a single mutant allele, showing dominant inheritance, and 2 families were compound heterozygous for R894X and another mutation, showing recessive inheritance. RT-PCR did not reveal any association between total CLCN1 mRNA 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, even compared to the recessive families. Duno et al. (2004) suggested that variation in allelic expression may be a modifier of disease expression and progression in myotonia congenita.
Raja Rayan et al. (2012) performed multiplex ligation-dependent probe amplification (MLPA) specific to the CLCN1 gene in 60 families with recessive myotonia congenita in whom either no mutations or only a single pathogenic CLCN1 mutation had been identified. The results were positive in 4 (6.7%) patients: 2 unrelated patients were found to have 2 different multiexon deletions within the CLCN1 gene on the second allele, and 2 additional patients had a homozygous duplication of exons 8 through 14 of the CLCN1 gene (118425.0020). The 2 patients with the duplication were both of Iraqi origin, but were unrelated. Both Iraqi patients had a severe form of the disorder with onset in infancy. Haplotype analysis suggested a founder effect for this duplication mutation. Raja Rayan et al. (2012) concluded that copy number variation involving the CLCN1 gene is an important genetic mechanism in patients with recessive myotonia congenita, and that MLPA analysis may aid in genetic counseling.
In 4 Costa Rican families with myotonia congenita, Vindas-Smith et al. (2016) identified mutations in the CLCN1 gene by bidirectional sequencing of the CLCN1 gene, with confirmation by RFLP-PCR. In 2 families in which the proband had Thomsen disease (families 1 and 4), heterozygous mutations were identified (F167L; Q412P, 118425.0022). In another family in which the proband had Thomsen disease (family 2), compound heterozygous mutations were identified (R105C and F167L). In a proband (family 3) with a myositis-like disorder, a variant of unknown significance (Q154R) was identified. Functional studies of CLCN1 with the F167L, R105C, or Q154R mutation did not show alterations of gating parameters or channel conductance. Functional studies of CLCN1 with the Q412P mutation expressed in Xenopus oocytes showed reduced surface expression and reduced current density. Vindas-Smith et al. (2016) concluded that the Q412P mutation induces a severe folding defect that leads to its degradation before it can dimerize with the wildtype subunit.
Altamura et al. (2018) evaluated the functional significance of 7 mutations in the C-terminal region of the CLCN1 gene associated with either autosomal dominant Thomsen disease or autosomal recessive Becker disease. CLCN1 with each mutation was transfected into HEK293 cells and analyzed with patch-clamp analysis. Five of the mutations were in the CBS2 domain (V829M, T832I, V851M, G859V, L861P) and 2 of the mutations were in the C-terminal peptide (P883T, V947E). Mutations located between residues 829 and 835 and in residue 883 resulted in alteration of voltage dependence. Mutations between residues 851 and 859 and in residue 947 resulted in a reduction of chloride currents. The results were consistent with a role for CBS2 in protein channel gating and demonstrated the importance of the C-peptide region in protein function and expression.
Suetterlin et al. (2022) assessed the function of 95 CLCN1 mutations, including 34 novel mutations, identified in 233 patients with myotonia congenita. Mutations in CLCN1 were assessed by transfection of cDNA with each mutation into Xenopus laevis oocytes and analyzed with 2-electrode voltage clamp assays. From a functional standpoint, mutations that altered voltage dependence of activation clustered in the first half of the transmembrane domains and mutations resulting in absent currents clustered in the second half of the transmembrane domain. In terms of assessment of clinical significance and inheritance patterns, mutations that resulted in dominant functional features clustered in the TM1 domain, and variants associated with recessive functional features and without a shift in voltage dependence of activation were clustered in the TM2 domain. Mutations in the intracellular domain were not associated with a dominant inheritance pattern. Suetterlin et al. (2022) concluded that functional characterization of CLCN1 mutations improves the assessment of their clinical implications.
Myotonic Dystrophy
Myotonic dystrophy (DM1; 160900) is caused by a trinucleotide repeat expansion of the DMPK gene (605377.0001). In DM, expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, Mankodi et al. (2002) showed that expression of expanded CUG repeats reduced the transmembrane chloride conductance to levels well below those expected to cause myotonia. The expanded CUG repeats triggered aberrant splicing of pre-mRNA for CLCN1, resulting in loss of the CLCN1 protein from the surface membrane. Mankodi et al. (2002) identified a similar defect in CLCN1 splicing and expression in DM1 and DM2 (602668). The authors proposed that a transdominant effect of mutant RNA on CLCN1 RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.
Charlet-B et al. (2002) demonstrated loss of CLCN1 mRNA and protein in DM1 skeletal muscle tissue due to aberrant splicing of the CLCN1 pre-mRNA. They showed that the splicing regulator, CUG-binding protein (CUGBP; 601074), which is elevated in DM1 striated muscle, bound to the CLCN1 pre-mRNA, and that overexpression of CUGBP in normal cells reproduced the aberrant pattern of CLCN1 splicing observed in DM1 skeletal muscle. Charlet-B et al. (2002) proposed that disruption of alternative splicing regulation causes a predominant pathologic feature of DM1.
Associations Pending Confirmation
See 118425.0021 for discussion of a possible association between variation in the CLCN1 gene and idiopathic generalized epilepsy (EIG; see 600669).
Aminoff et al. (1977) found that a subset of patients with myotonia congenita showed a marked decrement of the compound motor action potential (CMAP) with repeated stimulation compared to controls. Although the presence of decrement was not related to the degree of myotonia, it was usually observed in patients with autosomal recessive disease. Colding-Jorgensen et al. (2003) found that all 6 patients with the dominant P480L (118425.0006) mutation had CMAP decrements above 30%. In patients with the R894X (118425.0015) mutation, some had a large decrement, some had a slight decrement, and some had no change. Two patients with 2 CLCN1 mutations, 1 of whom carried an R894X mutation, had large decrements above 80%. Presence of decrement did not correlate with disease severity. Colding-Jorgensen et al. (2003) concluded that CMAP decrement may occur in dominant myotonia congenita and likely reflects the degree of chloride conduction reduction caused by particular mutations.
The Adr ('arrested development of righting') mouse, a model of autosomal recessive myotonia congenita, was found to be due to a mutation on mouse chromosome 6 (Rudel, 1990) in a region of the genome with homology of synteny to human chromosome 7q31-q35. The locus in the mouse is between those for Tcrb and Hox1. Steinmeyer et al. (1991) found that the Adr mouse phenotype was caused by a transposon insertion mutation that altered and inactivated the muscle-membrane chloride channel gene. The findings confirmed that the Adr mouse is an authentic model of Becker disease in the human.
Wu and Olson (2002) determined that Adr mice, which have an inactivated Clcn1 gene, showed an increased number of oxidative fibers, lacked glycolytic fibers, and showed muscle hypertrophy, similar to patients with Becker syndrome. By breeding Clcn1-null mice with mice harboring an Mef2 (600660)-dependent reporter gene, they found that the transcriptional activity of Mef2 was dramatically enhanced in myotonic muscle. Induction of Mef2 did not correlate with enhanced DNA-binding activity, but did correlate with activation of p38 Mapk (see 600289), an activator of Mef2, and with reduced expression of class II histone deacetylases (HDACs; see 605314), which repress Mef2 activity. Wu and Olson (2002) hypothesized that mutations in Clcn1 alter intracellular calcium levels, leading to the combined effects of class II Hdac deficiency and p38 Mapk activation, resulting in upregulation of Mef2 transcriptional activity followed by long-term changes in gene expression and to fiber-type transformation.
Beck et al. (1996) noted that the current hypotheses regarding the pathophysiology of autosomal dominant myotonia congenita, or Thomsen disease, were initially formulated from studies of the myotonic goat, an unusual breed afflicted with severe autosomal dominant congenital myotonia that closely resembles the human disease clinically and in its mode of inheritance. These animals are often referred to as 'fainting,' 'nervous,' 'stiff-legged,' or 'epileptic' goats because of their tendency to develop severe acute muscle stiffness and become immobile and often fall when attempting to make sudden forceful movements or when startled. The pathogenesis of myotonia in the goat was elucidated by Bryant and colleagues (Bryant, 1962, Lipicky and Bryant, 1966) who first described a severely diminished resting chloride conductance in muscle fibers from affected animals. The same group (Adrian and Bryant, 1974) also demonstrated that myotonia could be produced in normal skeletal muscle fibers bathed in a chloride-free solution. Beck et al. (1996) demonstrated the molecular basis for the decreased muscle chloride conductance in this historically important animal model. They found a single nucleotide change (GCC to CCC), resulting in an ala885-to-pro (A885P) substitution in a conserved residue in the C terminus of the goat muscle chloride channel, 104 residues from the termination codon. Heterologous expression of the mutation demonstrated a substantial (+47 mV) shift in the midpoint of steady-state activation of the channel, resulting in a diminished channel open probability at voltages near the resting membrane potential of skeletal muscle.
In 3 brothers with autosomal recessive generalized myotonia congenita (Becker disease; 255700), born of consanguineous parents, Koch et al. (1992) identified a homozygous T-to-G transversion in the CLCN1 gene, resulting in a phe413-to-cys (F413C) substitution toward the end of putative membrane span D8. This residue lies in a highly conserved region of the channel protein that is predicted to form a membrane-spanning alpha helix and possibly a component of the permeation pore (George et al., 1993).
Koch et al. (1993) found the F413C missense mutation in 15% of chromosomes carrying a gene for recessive myotonia congenita.
In affected members of 3 unrelated families with autosomal dominant myotonia congenita (Thomsen disease; 160800), George et al. (1993) identified a G-to-A transition in the CLCN1 gene, resulting in a gly230-to-glu (G230E) substitution between the third and fourth predicted membrane-spanning segments. This glycine residue is conserved in all known members of this class of chloride channel proteins. The codon number used for this mutation was based on the available partial-length cDNA of CLCN1; when the full-length cDNA became known, the codon number was changed from 180 to 230 (George, 1997).
In functional expression studies, Fahlke et al. (1997) found that the G230E mutation caused substantial changes in anion and cation selectivity, as well as a fundamental change in rectification of the current-voltage relationship. Whereas wildtype channels were characterized by pronounced inward rectification and a characteristic pattern of selectivity, G230E exhibited outward rectification at positive potentials and a different pattern of selectivity. Furthermore, the cation-to-anion permeability ratio of the mutant was much greater than that of the wildtype channel.
In affected members of a German family with recessive myotonia (255700), Lorenz et al. (1994) identified compound heterozygosity for 2 mutations in the CLCN1 gene: a 979G-A transition in a splice consensus site at the end of exon 8, and a 1488G-T transversion in exon 14, resulting in an arg496-to-ser (R496S; 118425.0004). Functional expression of R496S cRNA in Xenopus oocytes yielded no detectable currents. Furthermore, it did not suppress wildtype currents in coexpression assay, confirming it as a recessive mutation. The G-to-A transition in exon 8 was stated to affect the last nucleotide of the exon. If this interfered with mRNA splicing at that exon/intron boundary, the translation product would be terminated by a stop codon after 51 additional amino acids or other splice sites in the intron might be used. Alternatively, if splicing were normal, this mutation would lead to a substitution of isoleucine for valine at position 327 (V327I). Since this residue is not conserved among the members of this gene family and most members have negatively charged glutamate residues at this position, it is unlikely that such a substitution would have a dramatic effect on channel function. This would argue for an aberrant splicing as the effect of the G979A mutation.
For discussion of the arg496-to-ser (R496S) mutation in the CLCN1 gene that was found in compound heterozygous state in affected members of a family with recessive myotonia (255700) by Lorenz et al. (1994), see 118425.0003.
In affected members of a family with Becker myotonia congenita (255700), Koch et al. (1994) identified a mutation in the CLCN1 gene, resulting in a gly482-to-arg (G482R) substitution. Interestingly, this mutation producing a recessive phenotype is only 2 codons removed from a pro480-to-leu (P480L; 118425.0006) mutation which results in the dominant Thomsen type of myotonia congenita.
In affected members of Thomsen's own family (Thomsen, 1876; Thomasen, 1948) with autosomal dominant myotonia congenita (160800), Steinmeyer et al. (1994) identified a heterozygous mutation in the CLCN1 gene, resulting in a pro480-to-leu (P480L) substitution. Functional expression studies showed that the P480L mutation dramatically inhibited normal CLCN1 channel function via a dominant-negative effect.
Koch et al. (1994) also reported the P480L mutation as causative of Thomsen disease.
Pusch et al. (1995) transfected cDNA bearing the P480L mutation into Xenopus oocytes, demonstrating a large 90-mV shift of the gating toward positive voltages. In further structure studies, they replaced isoleucine 290 by 18 different amino acids. Substitution with valine shifted the gating by -17 millivolts. In all other replacements, the gating was either shifted to more positive voltages or resulted in no current above background.
Colding-Jorgensen et al. (2003) found that all 6 patients with the dominant P480L mutation had CMAP decrements above 30%, which the authors suggested was correlated with the large voltage shift conferred by the mutation.
In 2 brothers with a mild form of dominant myotonia, referred to as myotonia levior (see 160800), Lehmann-Horn et al. (1995) identified a 1655A-G transition in exon 15 of the CLCN1 gene, resulting in a gln552-to-arg (Q552R) substitution. Their affected mother also had the mutation. The findings indicated that myotonia levior is a variant or allelic form of Thomsen disease.
By functional expression studies, Ryan et al. (2002) demonstrated that CLCN1 channels with the Q552R mutation were formed normally, but had altered gating properties. Voltage dependence of the mutant channels was shifted by more than +90 mV compared to wildtype channels, resulting in a reduction in the open probability of the channel.
In affected members of a family with Thomsen myotonia (160800), Lehmann-Horn et al. (1995) identified an 870C-G transversion in the CLCN1 gene, resulting in an ile290-to-met (I290M) substitution.
In patients with Becker myotonia (255700), Meyer-Kleine et al. (1994) identified a 14-bp deletion in exon 13 of the CLCN1 gene.
In a family in which the index patient and his mother had been examined by Becker (1977), who classified their disorder as dominant myotonia congenita, Lehmann-Horn et al. (1995) found that the proband was homozygous for a 14-bp deletion (involving nucleotides 1437-1450) in exon 13 of the CLCN1 gene. Both nonmyotonic sons of the index patient were heterozygous for the deletion.
In French Canadian patients with recessive myotonia, Dupre et al. (2009) found that homozygosity for the 14-bp deletion resulted in a severe phenotype with generalized hypertrophy, moderate myotonia, and transient weakness.
In 2 sibs with autosomal recessive myotonia congenita (255700), Pusch et al. (1995) identified compound heterozygosity for 2 mutations in the CLCN1 gene: glu291-to-lys (E291K) and arg894-to-ter (R894X; 118425.0015). Functional expression studies showed that the E291K channels did not yield currents between -140 and 100 millivolts, indicating that this mutation totally abolished channel activity. In contrast to the mutation in the neighboring amino acid (I290M; 118425.0008), which acts as a dominant as a result of interactions with wildtype monomers, the E291K mutation is recessive. Whereas the I290M mutant shifts the voltage dependence of chloride channels positive (via homomers or heteromers with wildtype subunits), the E291K mutation shows no evidence of interaction and does not shift the voltage dependence.
The arg317-to-gln (R317Q) mutation illustrates the resultant occurrence of either autosomal dominant myotonia congenita (160800) or autosomal recessive myotonia congenita (255700), depending on the family background. Meyer-Kleine et al. (1995) observed the R317Q mutation in dominant Thomsen myotonia congenita; Esteban et al. (1998) observed it in Becker myotonia congenita and pointed to other mutations that had been observed as a recessive or a dominant, depending on the particular family.
In a boy with Becker myotonia congenita (255700), Zhang et al. (2000) identified a C-to-T transition at codon 1495 in exon 14 of the CLCN1 gene, resulting in a gly499-to-arg (G499R) substitution in the putative transmembrane domain 10 of the CLCN1 protein. In contrast to normal CLCN1 channels that deactivate upon hyperpolarization, functional expression of G499R CLCN1 yielded a hyperpolarization-activated chloride current when measured in the presence of a high intracellular chloride concentration. Current was abolished when measured with a physiologic chloride transmembrane gradient. Electrophysiologic analysis of other gly449 mutants suggested that the positive charge introduced by the G499R mutation may be responsible for this unique gating behavior.
In 2 African American sibs with autosomal recessive myotonia congenita (255700), Nagamitsu et al. (2000) identified compound heterozygosity for 2 mutations in the CLCN1 gene: a 1-bp insertion (831insG) in exon 7, resulting in a premature termination codon at codon 289, and a C-to-T transition in exon 23, resulting in a pro932-to-leu (P932L; 118425.0014) substitution. In addition to generalized myotonia and proximal muscle hypertrophy, the sibs also displayed progressive muscle weakness, joint contractures, and dystrophic muscle pathology.
For discussion of the pro932-to-leu (P932L) mutation in the CLCN1 gene that was found in compound heterozygous state in sibs with autosomal recessive myotonia congenita (255700) by Nagamitsu et al. (2000), see 118425.0013.
For discussion of the arg894-to-ter (R894X) mutation in the CLCN1 gene that was found in compound heterozygous state in sibs with autosomal recessive myotonia congenita (255700) by Pusch et al. (1995), see 118425.0010.
In patients with both autosomal recessive and autosomal dominant (160800) myotonia congenita, Meyer-Kleine et al. (1995) identified a mutation in the CLCN1 gene, resulting in an R894X substitution. Functional expression of the R894X mutant in Xenopus oocytes revealed a large reduction, but not complete abolition, of chloride currents. Further, it had a weak dominant-negative effect on wildtype currents in coexpression studies. Reduction of currents predicted for heterozygous carriers were close to the borderline value, sufficient to elicit myotonia.
Sun et al. (2001) found a carrier frequency of 0.87% for the R894X mutation in the northern Scandinavian population.
In a French Canadian family with myotonia, Dupre et al. (2009) found that the R894X mutation could be expressed in a semidominant or recessive manner. The proband, who was heterozygous for the R894X mutation, had muscle stiffness and mild warm-up phenomenon, but no significant percussion myotonia and no myotonia on EMG. In contrast, her daughters, who were compound heterozygous for the R894X and R300X (118425.0017) mutations, showed a moderately severe phenotype with generalized hypertrophy consistent with autosomal recessive Becker myotonia. This compound heterozygous genotype showed resistance to phenytoin, mexiletine, and quinine.
In affected members of a family with autosomal dominant myotonia congenita (160800), Colding-Jorgensen et al. (2003) identified a heterozygous A-to-G transition in the CLCN1 gene, resulting in a met128-to-val (M128V) substitution.
For discussion of the arg300-to-ter (R300X) mutation in the CLCN1 gene that was found in compound heterozygous state in patients with autosomal recessive myotonia congenita (255700) by Dupre et al. (2009), see 118425.0015.
In 2 French Canadian women with autosomal dominant myotonia congenita (160800), Dupre et al. (2009) identified a heterozygous ser189-to-phe (S189F) substitution in the CLCN1 gene. Both women had mild fluctuating myotonia and mild muscle hypertrophy and reported aggravation of symptoms with menstrual periods and pregnancy.
Dupre et al. (2009) identified a heterozygous or homozygous trp433-to-arg (W433R) substitution in the CLCN1 gene in French Canadian patients with autosomal dominant (160800) and recessive (255700) myotonia, respectively. The recessive phenotype was characterized by severe myotonia, dysphagia, generalized hypertrophy predominant in lower limb muscles, and the warm-up phenomenon.
In 2 unrelated Iraqi women with severe infantile-onset myotonia congenita (255700), Raja Rayan et al. (2012) identified a homozygous duplication of exons 8 through 14 of the CLCN1 gene, predicted to result in a frameshift. Both patients came from consanguineous families and had multiple affected family members. The duplication was identified by multiplex ligation-dependent probe amplification (MLPA) specific to the CLCN1 gene, and was not found in 124 control chromosomes or in a variant database. Haplotype analysis suggested a founder effect for this duplication mutation. Raja Rayan et al. (2012) concluded that copy number variation involving the CLCN1 gene is an important genetic mechanism in patients with recessive myotonia congenita, and that MLPA analysis may aid in genetic counseling.
This variant is classified as a variant of unknown significance because its contribution to idiopathic generalized epilepsy (EIG; see 600669) has not been confirmed.
In a 26-year-old Italian woman with EIG, Chen et al. (2013) identified a de novo heterozygous c.2926C-T transition (c.2926C-T, NM_000083) in exon 23 of the CLCN1 gene, resulting in an arg976-to-ter (R976X) substitution and truncation of the distal C terminus by 12 residues. The mutation, which was found by exome sequencing of 291 patients with epilepsy, was not found in the dbSNP or 1000 Genomes Project databases. The patient had generalized pharmacoresistant epilepsy with mixed seizure types, including generalized tonic-clonic and absence seizures. Her first seizure occurred during a febrile illness at age 11 months. EEG repeatedly showed generalized spike-wave discharges. In addition, she presented with myotonic writer's cramp at age 9 years, which subsequently resolved. EMG as an adult showed no evidence of myotonic discharges. Brain MRI and cognitive function were normal. Functional studies of the variant were not performed, but Chen et al. (2013) found expression of the CLCN1 gene in multiple human brain regions, and suggested that the mutation identified in this patient could result in neuronal hyperexcitability, thus contributing to the seizure phenotype.
In a Costa Rican patient (family 4-CR14) with autosomal dominant myotonia congenita (160800), Vindas-Smith et al. (2016) identified a heterozygous c.1235A-C transversion in exon 11 of the CLCN1 gene, resulting in a gln412-to-pro (Q412P) substitution. The mutation, which was identified by bidirectional sequencing of the CLCN1 gene and confirmed by RFLP-PCR, was also found in the patient's asymptomatic (self-reported) mother and 2 sibs. Functional studies of CLCN1 with the Q412P mutation expressed in Xenopus oocytes showed reduced surface expression and reduced current density but did not display a dominant-negative effect when coexpressed with wildtype CLCN1.
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