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International Journal of Molecular... May 2017The flow of intracellular calcium (Ca) is critical for the activation and regulation of important biological events that are required in living organisms. As the major... (Review)
Review
The flow of intracellular calcium (Ca) is critical for the activation and regulation of important biological events that are required in living organisms. As the major Ca repositories inside the cell, the endoplasmic reticulum (ER) and the sarcoplasmic reticulum (SR) of muscle cells are central in maintaining and amplifying the intracellular Ca signal. The morphology of these organelles, along with the distribution of key calcium-binding proteins (CaBPs), regulatory proteins, pumps, and receptors fundamentally impact the local and global differences in Ca release kinetics. In this review, we will discuss the structural and morphological differences between the ER and SR and how they influence localized Ca release, related diseases, and the need for targeted genetically encoded calcium indicators (GECIs) to study these events.
Topics: Animals; Calcium Channels; Calcium Signaling; Calcium-Binding Proteins; Humans; Malignant Hyperthermia; Myotonia Congenita; Sarcoplasmic Reticulum; Tachycardia
PubMed: 28489021
DOI: 10.3390/ijms18051024 -
Journal of Genetics Sep 2019Myotonia congenita (MC) is a Mendelian inherited genetic disease caused by the mutations in the gene, encoding the main skeletal muscle ion chloride channel (ClC-1)....
Myotonia congenita (MC) is a Mendelian inherited genetic disease caused by the mutations in the gene, encoding the main skeletal muscle ion chloride channel (ClC-1). The clinical diagnosis of MC should be suspected in patients presenting myotonia, warm-up phenomenon, a characteristic electromyographic pattern, and/or family history. Here, we describe the largest cohort of MC Spanish patients including their relatives (up to 102 individuals). Genetic testing was performed by sequencing and multiplex ligation-dependent probe amplification (MLPA). Analysis of selected exons of the gene, causing paramyotonia congenita, was also performed. Mutation spectrum and analysis of a likely founder effect of c.180+3A>T was achieved by haplotype analysis and association tests. Twenty-eight different pathogenic variants were found in the gene, of which 21 were known mutations and seven not described. Gross deletions/duplications were not detected. Four probands had a pathogenic variant in SCN4A. Two main haplotypes were detected in c.180+3A>T carriers and no statistically significant differences were detected between case and control groups regarding the type of haplotype and its frequencies. A diagnostic yield of 51% was achieved; of which 88% had pathogenic variants in and 12% in . The existence of a c.180+3A>T founder effect remains unsolved.
Topics: Chloride Channels; Cohort Studies; Exons; Female; Founder Effect; Haplotypes; Humans; Male; Muscle, Skeletal; Mutation; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide; Spain
PubMed: 31544778
DOI: No ID Found -
ELife Apr 2021In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain...
In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to -25 to -35 mV in the genetic and pharmacologic models of Becker disease. Both Na and Ca currents contribute to plateau potentials. Na persistent inward current (NaPIC) through Na1.4 channels is the key trigger of plateau potentials and current through Ca1.1 Ca channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita.
Topics: Animals; Disease Models, Animal; Female; Male; Membrane Potentials; Mice; Myotonia Congenita; Sodium
PubMed: 33904400
DOI: 10.7554/eLife.65691 -
Journal of the Neurological Sciences Apr 2017Non-dystrophic (NDMs) and Dystrophic Myotonias (DMs) are diseases characterized by the presence of myotonia with or without muscle weakness. A standardized myotonia...
Non-dystrophic (NDMs) and Dystrophic Myotonias (DMs) are diseases characterized by the presence of myotonia with or without muscle weakness. A standardized myotonia assessment is important to more objectively quantify the handgrip myotonia. We screened 10 patients affected by NDM and 10 patients with DM, using the sensor-engineered glove (SEG). The time required to perform a complete finger extension (grip myotonia time, GMT) at maximum velocity (MV) after maximum voluntary contraction (MVC) was evaluated through an ad hoc protocol including rest, exercise, and ice effects on handgrip myotonia. We observed a general trend to GMT increase when applying the ice block and a GMT decrease when repeating GM movements, at individual level in both NDM and DM patients. SEG is an automated, non-invasive, quick, and easy technique for evaluating handgrip myotonia in NDM and DM patients. SEG could, therefore, be considered a promising tool to evaluate myotonia and monitor treatment efficacy for clinical trials.
Topics: Adolescent; Adult; Biomedical Engineering; Diagnostic Techniques, Neurological; Equipment and Supplies; Female; Hand Strength; Humans; Male; Middle Aged; Muscle Contraction; Muscle, Skeletal; Myotonia; Young Adult
PubMed: 28320154
DOI: 10.1016/j.jns.2017.01.038 -
Annals of Neurology Sep 2017Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes...
OBJECTIVE
Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC-1 current.
METHODS
In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita.
RESULTS
Intracellular recordings revealed a slow afterdepolarization (AfD) that triggers myotonic action potentials. The AfD is well explained by a tetrodotoxin-sensitive and voltage-dependent Na persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC.
INTERPRETATION
This work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na current. Ann Neurol 2017;82:385-395.
Topics: Action Potentials; Animals; Disease Models, Animal; Mice; Muscle Contraction; Muscle, Skeletal; Myotonia Congenita; Sodium Channels
PubMed: 28833464
DOI: 10.1002/ana.25017 -
Obstetric Medicine Dec 2020Paramyotonia congenita is a rare autosomal dominant non-dystrophic myopathy caused by mutations in the SNC4A gene, which encodes for the voltage-gated sodium channel in...
Paramyotonia congenita is a rare autosomal dominant non-dystrophic myopathy caused by mutations in the SNC4A gene, which encodes for the voltage-gated sodium channel in skeletal muscle. Symptom onset is typically during early childhood and is characterised by myotonia followed by flaccid paralysis or weakness, usually exacerbated by repeated muscle contractions or cold temperatures. Pregnancy has been reported to increase symptoms of myotonia; however, there is limited information in the literature regarding the possible effects of paramyotonia congenita on pregnancy and labour. We present a successful case of a 20-year-old primigravida with confirmed paramyotonia congenita and review the literature regarding paramyotonia congenita during pregnancy.
PubMed: 33343696
DOI: 10.1177/1753495X18816171 -
The Journal of Pediatrics May 2022
Topics: Child; Humans; Male; Myotonia Congenita
PubMed: 34953819
DOI: 10.1016/j.jpeds.2021.12.039 -
Neuromuscular Disorders : NMD Mar 2023We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population...
We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population impact, planning for treatment needs and future clinical trials. Skeletal muscle channelopathies include myotonia congenita (MC), sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (hyperPP), hypokalemic periodic paralysis (hypoPP) and Andersen- Tawil Syndrome (ATS). Patients referred to the UK national referral centre for skeletal muscle channelopathies and living in UK were included to calculate the minimum point prevalence using the latest data from the Office for National Statistics population estimate. We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981-1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123-1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 - 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098-0.102). There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies.
Topics: Humans; Paralysis, Hyperkalemic Periodic; Hypokalemic Periodic Paralysis; Prevalence; Channelopathies; High-Throughput Nucleotide Sequencing; NAV1.4 Voltage-Gated Sodium Channel; Mutation; Muscle, Skeletal; Myotonic Disorders; Andersen Syndrome
PubMed: 36796140
DOI: 10.1016/j.nmd.2023.01.007 -
The Korean Journal of Physiology &... Jul 2017Myotonia congenita (MC) is a genetic disease that displays impaired relaxation of skeletal muscle and muscle hypertrophy. This disease is mainly caused by mutations of...
Myotonia congenita (MC) is a genetic disease that displays impaired relaxation of skeletal muscle and muscle hypertrophy. This disease is mainly caused by mutations of that encodes human skeletal muscle chloride channel (CLC-1). CLC-1 is a voltage gated chloride channel that activates upon depolarizing potentials and play a major role in stabilization of resting membrane potentials in skeletal muscle. In this study, we report 4 unrelated Korean patients diagnosed with myotonia congenita and their clinical features. Sequence analysis of all coding regions of the patients was performed and mutation, R47W and A298T, was commonly identified. The patients commonly displayed transient muscle weakness and only one patient was diagnosed with autosomal dominant type of myotonia congenita. To investigate the pathological role of the mutation, electrophysiological analysis was also performed in HEK 293 cells transiently expressing homo- or heterodimeric mutant channels. The mutant channels displayed reduced chloride current density and altered channel gating. However, the effect of A298T on channel gating was reduced with the presence of R47W in the same allele. This analysis suggests that impaired CLC-1 channel function can cause myotonia congenita and that R47W has a protective effect on A298T in relation to channel gating. Our results provide clinical features of Korean myotonia congenita patients who have the heterozygous mutation and reveal underlying pathophyological consequences of the mutants by taking electrophysiological approach.
PubMed: 28706458
DOI: 10.4196/kjpp.2017.21.4.439 -
International Journal of Molecular... Aug 2021The troponin complex is a key regulator of muscle contraction. Multiple variants in skeletal troponin encoding genes result in congenital myopathies. has been... (Review)
Review
The troponin complex is a key regulator of muscle contraction. Multiple variants in skeletal troponin encoding genes result in congenital myopathies. has been implicated in a novel congenital myopathy, and in distal arthrogryposis (DA), and and in nemaline myopathy (NEM). Variants in skeletal troponin encoding genes compromise sarcomere function, e.g., by altering the Ca sensitivity of force or by inducing atrophy. Several potential therapeutic strategies are available to counter the effects of variants, such as troponin activators, introduction of wild-type protein through AAV gene therapy, and myosin modulation to improve muscle contraction. The mechanisms underlying the pathophysiological effects of the variants in skeletal troponin encoding genes are incompletely understood. Furthermore, limited knowledge is available on the structure of skeletal troponin. This review focusses on the physiology of slow and fast skeletal troponin and the pathophysiology of reported variants in skeletal troponin encoding genes. A better understanding of the pathophysiological effects of these variants, together with enhanced knowledge regarding the structure of slow and fast skeletal troponin, will direct the development of treatment strategies.
Topics: Animals; Humans; Muscle Contraction; Myotonia Congenita; Sarcomeres; Troponin
PubMed: 34502093
DOI: 10.3390/ijms22179187