Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene

Mazón, Marı́a J.; Barros, Francisco; Peña, Pilar de la; Quesada, Juan F.; Escudero, Adela; Cobo, Ana Maria; Pascual, Pascual; Gutiérrez-Rivas, Eduardo; Guillén, Encarna; Arpa, Javier; Eraso, Pilar; Portillo, Francisco; Molano, Jesús

doi:10.1016/j.nmd.2011.10.013

Cited by 33 publications

(41 citation statements)

References 32 publications

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“…; Mazon et al . ). Therefore, one additional hypothesis for the occurrence of a severe Becker phenotype in patients carrying both R894X and V640G may be that the R894X exhausts V640G by enhancing the degradation of heterodimers, thereby reducing further the sarcolemma chloride conductance.…”

Section: Discussionmentioning

confidence: 97%

ClC‐1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype–phenotype correlation

Imbrici

Maggi

Mangiatordi

et al. 2015

The Journal of Physiology

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Key pointsr Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes.r Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant-negative effect on the wild-type (WT) subunit.r Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R.r Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only).r Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.Abstract Myotonia congenita is an inherited disease caused by loss-of-function mutations of the skeletal muscle ClC-1 chloride channel, characterized by impaired muscle relaxation after contraction and stiffness. In the present study, we provided an in-depth characterization of F484L, a mutation previously identified in dominant myotonia, in order to define the genotype-phenotype correlation, and to elucidate the contribution of this pore residue to the mechanisms of ClC-1 gating. Patch-clamp recordings showed that F484L reduced chloride currents at every tested potential and dramatically right-shifted the voltage dependence of slow gating, thus contributing to the mild clinical phenotype of affected heterozygote carriers. Unlike dominant mutations located at the dimer interface, no dominant-negative effect was observed when F484L mutant subunits were co-expressed with wild type. Molecular dynamics simulations further revealed that F484L affected the slow gate by increasing the frequency and stability of the H-bond formation between the pore residue E232 and the R helix residue Y578. In addition, using patch-clamp electrophysiology, we characterized three other myotonic ClC-1 mutations. We proved that the dominant L198P mutation in the channel pore also right-shifted the voltage dependence of slow gating, recapitulating mild myotonia. The recessive V640G mutant drastically reduced channel function, which probably accounts for myotonia. In contrast, the recessive L628P mutant produced currents very similar to wild type, suggesting that the occurrence of the compound truncating mutation (Q812X) or other muscle-specific mechanisms accounted for the severe symptoms observed in this family. Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.

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Section: Discussionmentioning

confidence: 97%

ClC‐1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype–phenotype correlation

Imbrici

Maggi

Mangiatordi

et al. 2015

The Journal of Physiology

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“…Additionally, F484 orients its side chain in a configuration that lets us suggest a sandwich stacking with the central ring of 9‐AC (aromatic rings almost parallel). K231, R421 and F484 are all important residues for ClC‐1 activity (Fahlke et al ., ; Mazón et al ., ; Imbrici et al ., ). K231 contributes to the chloride‐selective pore, and K231A shows activation upon hyperpolarization and inverted voltage‐dependence (Fahlke et al ., , ).…”

Section: Resultsmentioning

confidence: 98%

“…A molecular dynamics simulation study suggested that mutating F484 affects the stability and frequency of H‐bond formation between E232 and Y578 residues (Imbrici et al ., ; Bennetts and Parker, ), thus impairing the two gating modes of ClC‐1 channels, protopore and common gating (Accardi and Pusch, ). The mutation R421C in helix L was found to reduce channel expression in a patient affected by myotonia congenita (Mazón et al ., ; Brugnoni et al ., ).…”

Section: Resultsmentioning

confidence: 99%

Mapping ligand binding pockets in chloride ClC‐1 channels through an integrated in silico and experimental approach using anthracene‐9‐carboxylic acid and niflumic acid

Altamura

Mangiatordi

Nicolotti

et al. 2018

British J Pharmacology

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“…28 A myotonic-associated mutation involving the adjacent codon (G230E/A/V) has been reported previously and mutation of glycine 230 to glutamate or alanine has been shown to yield functional channels. [29][30][31][32][33] Both residue V229 and G230 were in the E-F linker of CLC-1 7 . The G230E/A mutation causes substantial changes in ion selectivity as well as general permeation properties.…”

Section: Discussionmentioning

confidence: 99%

Myotonia congenita: novel mutations in CLCN1 gene

et al. 2015

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Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene

Cited by 33 publications

References 32 publications

ClC‐1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype–phenotype correlation

ClC‐1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype–phenotype correlation

Mapping ligand binding pockets in chloride ClC‐1 channels through an integrated in silico and experimental approach using anthracene‐9‐carboxylic acid and niflumic acid

Myotonia congenita: novel mutations in CLCN1 gene

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