Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands

Stunnenberg, Bas C.; Raaphorst, Joost; Deenen, J.C.W.; Links, Thera P.; Wilde, Arthur A.M.; Verbove, Dennis J; Kamsteeg, Erik‐Jan; Wijngaard, Arthur van den; Faber, Catharina G.; Wilt, Gert Jan van der; Engelen, B.G.M. van; Drost, Gea; Ginjaar, H.B.

doi:10.1016/j.nmd.2018.03.006

Cited by 44 publications

(32 citation statements)

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“…In our cohort PMC was the most frequent phenotype, accounting for almost a half of the whole population, followed by SCM and then by PP and Neonatal SCN4A, which represent a minority of the cases. Our data showing greater frequency of NDM than PP caused by SCN4A gene mutations are in agreement with previous studies on large cohorts of British and Dutch patients (5,17), although in our cohort PP seems to be underrepresented, being only 12.5% of the population.…”

Section: Discussionsupporting

confidence: 93%

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

et al. 2020

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Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. Maggi et al. SCN4A-Clinical Molecular and Features Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.

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Section: Discussionsupporting

confidence: 93%

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

et al. 2020

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“…In the present manuscript, we reported a detailed study of a ClC-1 mutation, p.G411C, identified in a Russian family. This mutation was detected only recently in a large group of patients with skeletal muscle channelopathies from the Netherlands ( 25 ). The mutation was associated with the frameshift mutation Phe404Hisfs * 16, suggesting a recessive trait, but was not functionally characterized.…”

Section: Discussionmentioning

confidence: 99%

Pathomechanisms of a CLCN1 Mutation Found in a Russian Family Suffering From Becker's Myotonia

et al. 2020

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Objective: Myotonia congenita (MC) is a rare muscle disease characterized by sarcolemma over-excitability inducing skeletal muscle stiffness. It can be inherited either as an autosomal dominant (Thomsen's disease) or an autosomal recessive (Becker's disease) trait. Both types are caused by loss-of-function mutations in the CLCN1 gene, encoding for ClC-1 chloride channel. We found a ClC-1 mutation, p.G411C, identified in Russian patients who suffered from a severe form of Becker's disease. The purpose of this study was to provide a solid correlation between G411C dysfunction and clinical symptoms in the affected patient. Methods: We provide clinical and genetic information of the proband kindred. Functional studies include patch-clamp electrophysiology, biotinylation assay, western blot analysis, and confocal imaging of G411C and wild-type ClC-1 channels expressed in HEK293T cells. Results: The G411C mutation dramatically abolished chloride currents in transfected HEK cells. Biochemical experiments revealed that the majority of G411C mutant channels did not reach the plasma membrane but remained trapped in the cytoplasm. Treatment with the proteasome inhibitor MG132 reduced the degradation rate of G411C mutant channels, leading to their expression at the plasma membrane. However, despite an increase in cell surface expression, no significant chloride current was recorded in the G411C-transfected cell treated with MG132, suggesting that this mutation produces non-functional ClC-1 chloride channels. Conclusion: These results suggest that the molecular pathophysiology of G411C is linked to a reduced plasma membrane expression and biophysical dysfunction of mutant channels, likely due to a misfolding defect. Chloride current abolition confirms that the mutation is responsible for the clinical phenotype.

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“…ATS is a rare genetic disease, with a prevalence of 0.08-0.1:100,000 (Horga et al, 2013;Stunnenberg et al, 2018). Cardiac ventricular arrhythmias may include prolonged QT interval, prominent U-wave or ventricular ectopy.…”

Section: Phenotypic Variability In Atsmentioning

confidence: 99%

Andersen–Tawil Syndrome Is Associated With Impaired PIP2 Regulation of the Potassium Channel Kir2.1

et al. 2020

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Andersen-Tawil syndrome (ATS) type-1 is associated with loss-of-function mutations in KCNJ2 gene. KCNJ2 encodes the tetrameric inward-rectifier potassium channel Kir2.1, important to the resting phase of the cardiac action potential. Kir-channels' activity requires interaction with the agonist phosphatidylinositol-4,5-bisphosphate (PIP 2). Two mutations were identified in ATS patients, V77E in the cytosolic N-terminal "slide helix" and M307V in the C-terminal cytoplasmic gate structure "G-loop." Current recordings in Kir2.1-expressing HEK cells showed that each of the two mutations caused Kir2.1 lossof-function. Biotinylation and immunostaining showed that protein expression and trafficking of Kir2.1 to the plasma membrane were not affected by the mutations. To test the functional effect of the mutants in a heterozygote set, Kir2.1 dimers were prepared. Each dimer was composed of two Kir2.1 subunits joined with a flexible linker (i.e. WT-WT, WT dimer; WT-V77E and WT-M307V, mutant dimer). A tetrameric assembly of Kir2.1 is expected to include two dimers. The protein expression and the current density of WT dimer were equally reduced to~25% of the WT monomer. Measurements from HEK cells and Xenopus oocytes showed that the expression of either WT-V77E or WT-M307V yielded currents of only about 20% compared to the WT dimer, supporting a dominant-negative effect of the mutants. Kir2.1 sensitivity to PIP 2 was examined by activating the PIP 2 specific voltage-sensitive phosphatase (VSP) that induced PIP 2 depletion during current recordings, in HEK cells and Xenopus oocytes. PIP 2 depletion induced a stronger and faster decay in Kir2.1 mutant dimers current compared to the WT dimer. BGP-15, a drug that has been demonstrated to have an anti-arrhythmic effect in mice, stabilized the Kir2.1 current amplitude following VSP-induced PIP 2 depletion in cells expressing WT or mutant dimers. This study underlines the implication of mutations in cytoplasmic regions of Kir2.1. A newly developed calibrated VSP activation protocol enabled a quantitative assessment of changes in PIP 2 regulation caused by the mutations. The results suggest an impaired function and a dominant-negative effect of the Kir2.

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Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands

Cited by 44 publications

References 21 publications

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

Pathomechanisms of a CLCN1 Mutation Found in a Russian Family Suffering From Becker's Myotonia

Andersen–Tawil Syndrome Is Associated With Impaired PIP2 Regulation of the Potassium Channel Kir2.1

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