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Hum Mutat. 2016 Jan;37(1):74-83. doi: 10.1002/humu.22916. Epub 2015 Oct 28.

Identification and Functional Characterization of CLCN1 Mutations Found in Nondystrophic Myotonia Patients.

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Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica.
Istituto di Biofisica, CNR, Via De Marini 6, Genova, Italy.
Centro de Investigación en Neurociencias (CIN), Universidad de Costa Rica, San José, Costa Rica.
Escuela de Medicina, Universidad de Costa Rica, Curridabat, San José, Costa Rica.
Laboratorio de Neurofisiología (Neurolab), Curridabat, San José, Costa Rica.
Departament de Ciències Fisiològiques II, Unitat de Fisiologia, Universitat de Barcelona, Carrer Feixa Llarga s/n, L'Hospitalet de Llobregat, Barcelona, Spain.
U-750, Centro de Investigación en red de enfermedades raras (CIBERER), ISCIII, Barcelona, Spain.


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.


dominant-negative; electrophysiology; myotonia; protein folding; surface expression

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