Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Maggi, Lorenzo; Bonanno, Silvia; Altamura, Concetta; Desaphy, Jean-François

doi:10.3390/cells10061521

Cited by 30 publications

(30 citation statements)

References 269 publications

(369 reference statements)

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“…Therefore, ATS should always be considered even in patients with only periodic paralysis or cardiac arrhythmias. Approximately 60% of ATS cases have causal variants in KCNJ2 (6,14). Most KCNJ2 pathogenic variants in ATS are missense variants (1,6) that result in loss of function of the Kir2.1 channel and is expressed in skeletal muscle, heart, and bone.…”

Section: Discussionmentioning

confidence: 99%

“…Most KCNJ2 pathogenic variants in ATS are missense variants (1,6) that result in loss of function of the Kir2.1 channel and is expressed in skeletal muscle, heart, and bone. This channel plays a role in prolonged depolarization of the action potential, and thereby cause periodic paralysis and cardiac arrhythmia (14). Additionally, KCNJ2 variants can affect skeletal dysmorphic features because KCNJ2 is expressed during the early stages of craniofacial development in Xenopus and mice (15).…”

Section: Discussionmentioning

confidence: 99%

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Andersen–Tawil Syndrome With Novel Mutation in KCNJ2: Case Report

Yim

Kim

et al. 2022

Front. Pediatr.

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Andersen–Tawil syndrome (ATS) is a rare autosomal dominant disorder characterized by a classic symptom triad: periodic paralysis, ventricular arrhythmias associated with prolonged QT interval, and dysmorphic skeletal and facial features. Pathogenic variants of the inwardly rectifying potassium channel subfamily J member 2 (KCNJ2) gene have been linked to the ATS. Herein, we report a novel KCNJ2 causative variant in a proband and her father showing different ATS-associated symptoms. A 15-year-old girl was referred because of episodic weakness and periodic paralysis in both legs for 2–3 months. The symptoms occurred either when she was tired or after strenuous exercise. These attacks made walking or climbing stairs difficult and lasted from one to several days. She had a short stature (142 cm, <3rd percentile) and weighed 40 kg. The proband also showed orbital hypertelorism, dental crowding, mandibular hypoplasia, fifth-digit clinodactyly, and small hands. Scoliosis in the thoracolumbar region was detected by chest X-ray. Since she was 7 years old, she had been treated for arrhythmia-associated long QT interval and underwent periodic echocardiography. Brain MRI revealed cerebrovascular abnormalities indicating absence or hypoplasia of bilateral internal carotid arteries, and compensation of other collateral vessels was observed. There were no specific findings related to intellectual development. The proband's father also had a history of periodic paralysis similar to the proband. He did not show any cardiac symptoms. Interestingly, he was diagnosed with hyperthyroidism during an evaluation for paralytic symptoms. Clinical exome sequencing revealed a novel heterozygous missense variant: Chr17(GRCh37):g.68171593A>T, NM_000891.2:c.413A>T, p.(Glu138Val) in KCNJ2 in the proband and the proband's father.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Andersen–Tawil Syndrome With Novel Mutation in KCNJ2: Case Report

Yim

Kim

et al. 2022

Front. Pediatr.

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“…In this hypothetical scenario, the ability of specialized ion channels to sense physical (e.g., voltage, pressure, temperature) and chemical (e.g., neurotransmitters, pH, divalent cations) would have allowed for superior selectivity, control, spatial and temporal segregation, and modulation of excitability. Such exquisite level of control would eventually become essential for the fitness and survival of modern unicellular and multicellular organisms, which explains the vast number of genetic and acquired (autoimmune and inflammatory) channelopathies affecting human health ( Capecchi et al, 2019 ; Allen et al, 2020 ; Kessi et al, 2021 ; Maggi et al, 2021 ; Mantegazza et al, 2021 ).…”

Section: The “Channel-less World”mentioning

confidence: 99%

Bio-Mimicking, Electrical Excitability Phenomena Associated With Synthetic Macromolecular Systems: A Brief Review With Connections to the Cytoskeleton and Membraneless Organelles

Wnek

Costa

Kozawa

2022

Front. Mol. Neurosci.

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Electrical excitability of cells, tissues and organs is a fundamental phenomenon in biology and physiology. Signatures of excitability include transient currents resulting from a constant or varying voltage gradient across compartments. Interestingly, such signatures can be observed with non-biologically-derived, macromolecular systems. Initial key literature, dating to roughly the late 1960’s into the early 1990’s, is reviewed here. We suggest that excitability in response to electrical stimulation is a material phenomenon that is exploited by living organisms, but that is not exclusive to living systems. Furthermore, given the ubiquity of biological hydrogels, we also speculate that excitability in protocells of primordial organisms might have shared some of the same molecular mechanisms seen in non-biological macromolecular systems, and that vestigial traces of such mechanisms may still play important roles in modern organisms’ biological hydrogels. Finally, we also speculate that bio-mimicking excitability of synthetic macromolecular systems might have practical biomedical applications.

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“…They span a continuum of altered membrane excitability and form the group of muscle Na + channelopathies, which are ultra-rare diseases with a prevalence estimated to be around 1–2/100,000 ( Horga et al, 2013 ; Stunnenberg et al, 2018a ). More than 70 GoF mutations in SCN4A , all missense, have been reported in these diseases ( Cannon, 2018 ; Maggi et al, 2021 ). A few are de novo, especially those causing neonatal forms of life-threatening myotonia (severe neonatal episodic laryngospasm or SNEL, myotonia permanens ) if not treated with Na v blockers ( Lion-Francois et al, 2010 ; Lehmann-Horn et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…The properties of SCN4A GoF mutations on Na v 1.4 gating behavior have been well studied using heterologous cell expression systems, mouse models and computer simulations, providing the community with pathophysiological mechanisms. Exhaustive structure-function aspects of Na v 1.4 channels, Na v 1.4 GoF mutations and related channelopathies are well discussed in recent reviews and are not the scope here ( Cannon, 2018 ; Catterall et al, 2020 ; Maggi et al, 2021 ; Mantegazza et al, 2021 ; Meisler et al, 2021 ). Briefly, all GoF missense mutations except those resulting in hypokalemic periodic paralyses (HOKPP or HypoPP, type 2 OMIM # 613,345) enhance activation or impair fast inactivation of Na v 1.4.…”

Section: Introductionmentioning

confidence: 99%

New Challenges Resulting From the Loss of Function of Nav1.4 in Neuromuscular Diseases

Nicole

Lory

2021

Front. Pharmacol.

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The voltage-gated sodium channel Nav1.4 is a major actor in the excitability of skeletal myofibers, driving the muscle force in response to nerve stimulation. Supporting further this key role, mutations in SCN4A, the gene encoding the pore-forming α subunit of Nav1.4, are responsible for a clinical spectrum of human diseases ranging from muscle stiffness (sodium channel myotonia, SCM) to muscle weakness. For years, only dominantly-inherited diseases resulting from Nav1.4 gain of function (GoF) were known, i.e., non-dystrophic myotonia (delayed muscle relaxation due to myofiber hyperexcitability), paramyotonia congenita and hyperkalemic or hypokalemic periodic paralyses (episodic flaccid muscle weakness due to transient myofiber hypoexcitability). These last 5 years, SCN4A mutations inducing Nav1.4 loss of function (LoF) were identified as the cause of dominantly and recessively-inherited disorders with muscle weakness: periodic paralyses with hypokalemic attacks, congenital myasthenic syndromes and congenital myopathies. We propose to name this clinical spectrum sodium channel weakness (SCW) as the mirror of SCM. Nav1.4 LoF as a cause of permanent muscle weakness was quite unexpected as the Na+ current density in the sarcolemma is large, securing the ability to generate and propagate muscle action potentials. The properties of SCN4A LoF mutations are well documented at the channel level in cellular electrophysiological studies However, much less is known about the functional consequences of Nav1.4 LoF in skeletal myofibers with no available pertinent cell or animal models. Regarding the therapeutic issues for Nav1.4 channelopathies, former efforts were aimed at developing subtype-selective Nav channel antagonists to block myofiber hyperexcitability. Non-selective, Nav channel blockers are clinically efficient in SCM and paramyotonia congenita, whereas patient education and carbonic anhydrase inhibitors are helpful to prevent attacks in periodic paralyses. Developing therapeutic tools able to counteract Nav1.4 LoF in skeletal muscles is then a new challenge in the field of Nav channelopathies. Here, we review the current knowledge regarding Nav1.4 LoF and discuss the possible therapeutic strategies to be developed in order to improve muscle force in SCW.

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Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Cited by 30 publications

References 269 publications

Andersen–Tawil Syndrome With Novel Mutation in KCNJ2: Case Report

Andersen–Tawil Syndrome With Novel Mutation in KCNJ2: Case Report

Bio-Mimicking, Electrical Excitability Phenomena Associated With Synthetic Macromolecular Systems: A Brief Review With Connections to the Cytoskeleton and Membraneless Organelles

New Challenges Resulting From the Loss of Function of Nav1.4 in Neuromuscular Diseases

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