Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia

Furby, Alain; Vicart, Savine; Camdessanché, J.-P.; Fournier, Emmanuel; Chabrier, Stéphane; Lagrue, Emmanuelle; Paricio, Caroline; Blondy, Patricia; Touraine, Renaud; Sternberg, Damien; Fontaine, Bertrand

doi:10.1016/j.nmd.2014.06.439

Cited by 29 publications

(22 citation statements)

References 33 publications

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“…Two patients with an additional heterozygous CLCN1 mutation did not differ largely from the rest of the patients, although heterozygous CLCN1 mutations have been found to modulate phenotype in sodium channel myotonia. 14 …”

Section: Discussionmentioning

confidence: 99%

Predominantly myalgic phenotype caused by the c.3466G>A p.A1156T mutation in SCN4A gene

et al. 2017

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Objective:To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation.Methods:Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in the SCN4A gene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p.A1156T mutation were studied in HEK293 cells with whole-cell patch clamp.Results:The main clinical manifestation in p.A1156T patients was not myotonia or periodic paralysis but exercise- and cold-induced muscle cramps, muscle stiffness, and myalgia. EMG myotonic discharges were detected in most but not all. Electrophysiologic compound muscle action potentials exercise test showed variable results. The p.A1156T mutation was identified in one patient in the DM2-neg group but not in the fibromyalgia group, making a total of 30 patients so far identified. Functional studies of the p.A1156T mutation showed mild attenuation of channel fast inactivation.Conclusions:The unspecific symptoms of myalgia stiffness and exercise intolerance without clinical myotonia or periodic paralysis in p.A1156T patients make the diagnosis challenging. The symptoms of milder SCN4A mutations may be confused with other similar myalgic syndromes, including fibromyalgia and myotonic dystrophy type 2.

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Section: Discussionmentioning

confidence: 99%

Predominantly myalgic phenotype caused by the c.3466G>A p.A1156T mutation in SCN4A gene

et al. 2017

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“… 150 Recently, a small group of patients with myotonia with heterozygous SCN4A mutations and single CLCN1 mutations were described, widening the genetic spectrum. 160 …”

Section: Channelopathies Of the Central Nervous Systemmentioning

confidence: 99%

Genetic neurological channelopathies: molecular genetics and clinical phenotypes

Spillane

Kullmann

Hanna

2015

J Neurol Neurosurg Psychiatry

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Evidence accumulated over recent years has shown that genetic neurological channelopathies can cause many different neurological diseases. Presentations relating to the brain, spinal cord, peripheral nerve or muscle mean that channelopathies can impact on almost any area of neurological practice. Typically, neurological channelopathies are inherited in an autosomal dominant fashion and cause paroxysmal disturbances of neurological function, although the impairment of function can become fixed with time. These disorders are individually rare, but an accurate diagnosis is important as it has genetic counselling and often treatment implications. Furthermore, the study of less common ion channel mutation-related diseases has increased our understanding of pathomechanisms that is relevant to common neurological diseases such as migraine and epilepsy. Here, we review the molecular genetic and clinical features of inherited neurological channelopathies.

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“…Although the p.F167L mutation (found in F1-CR3) has been found cosegregating with myotonic dystrophy type 2 (DM2) [Cardani et al, 2012], we did not perform the molecular diagnosis of DM2 in proband F1-CR3 because the clinical picture of the patient and the inheritance pattern (dominant in DM2) in the family suggested that the patient was affected with MC instead of DM2. There has been also one report describing the copresence of CLCN1 and SCN4A mutations in the same patient [Furby et al, 2014]. Thus, it might be possible that proband F1-CR3 carries a mutation in the SCN4A gene.…”

Section: Discussionmentioning

confidence: 98%

Identification and Functional Characterization ofCLCN1Mutations Found in Nondystrophic Myotonia Patients

et al. 2015

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Mutations in the gene coding for the skeletal muscle Cl(-) channel (CLCN1) lead to dominant or recessive myotonia. Here, we identified and characterized CLCN1 mutations in Costa Rican patients, who had been clinically diagnosed with myotonic dystrophy type 1 but who were negative for DM1 mutations. CLCN1 mutations c.501C>G, p.F167L and c.1235A>C, p.Q412P appeared to have recessive inheritance but patients had atypical clinical phenotypes; c.313C>T, p.R105C was found in combination with c.501C>G, p.F167L in an apparently recessive family and the c.461A>G, p.Q154R variant was associated with a less clear clinical picture. In Xenopus oocytes, none of the mutations exhibited alterations of fast or slow gating parameters or single channel conductance, and mutations p.R105C, p.Q154R, and p.F167L were indistinguishable from wild-type (WT). p.Q412P displayed a dramatically reduced current density, surface expression and exerted no dominant negative effect in the context of the homodimeric channel. Fluorescently tagged constructs revealed that p.Q412P is expressed inefficiently. Our study confirms p.F167L and p.R105C as myotonia mutations in the Costa Rican population, whereas p.Q154R may be a benign variant. p.Q412P most likely induces a severe folding defect, explaining the lack of dominance in patients and expression systems, but has WT properties once expressed in the plasma membrane.

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Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia

Cited by 29 publications

References 33 publications

Predominantly myalgic phenotype caused by the c.3466G>A p.A1156T mutation in SCN4A gene

Predominantly myalgic phenotype caused by the c.3466G>A p.A1156T mutation in SCN4A gene

Genetic neurological channelopathies: molecular genetics and clinical phenotypes

Identification and Functional Characterization ofCLCN1Mutations Found in Nondystrophic Myotonia Patients

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