Phenotypic Variability in Childhood of Skeletal Muscle Sodium Channelopathies

Yoshinaga, Harumi; Sakoda, Shunichi; Shibata, Takashi; Akiyama, Tomoyuki; Oka, Makio; Yuan, Jun Hui; Takashima, Hiroshi; Takahashi, Masanori; Kitamura, Tatsuya; Murakami, Norihiko; Kobayashi, Katsuhiro

doi:10.1016/j.pediatrneurol.2015.01.014

Cited by 9 publications

(8 citation statements)

References 17 publications

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“…28 The majority of gain-offunction variants in SCN4A occur within the VSR and pore with relative sparing of S5-S6. 29 In addition to the VSR, disorders associated with gain-of-function variants in SCN9A are also common in the DIII-DIV linker. 30 In contrast to the other sodium channels, loss-of-function variants in SCN4A and SCN9A are seen primarily when both alleles have a loss-of-function variant.…”

Section: Discussionmentioning

confidence: 99%

“…The table lists the most frequent associations but this is not exclusive. This has been compiled from multiple sources 5, 19, 26, 27, 29–32 ; ** Many missense variants in VSR have complicated functional effects with mixed electrophysiological changes but most exhibit some gain of function properties. Abbreviations: As in Table 1, in addition, DD = Developmental delay; ASD= Autism spectrum disorders; P = pore (S5, S5–6, S6); VSR= voltage sensor region (S3–4, S4; S4–5); TMO= transmembrane; het= heterozygous, hom=homozygous. …”

Section: Figurementioning

confidence: 99%

“…The table lists the most frequent associations but this is not exclusive. This has been compiled from multiple sources 5, 19, 26, 27, 29–32 ; …”

Section: Figurementioning

confidence: 99%

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Location: A surrogate for personalized treatment of sodium channelopathies

Holland

Bouley

Horn

2018

Annals of Neurology

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Voltage-gated sodium channels have been implicated in numerous inherited paroxysmal disorders of the nervous system, muscle, and heart. Our goal is to provide a framework that helps neurologists understand the clinical and treatment implications of sodium channel variants they encounter in clinical practice. This will be accomplished through our objectives of (1) recognizing the relationship between location of a missense sodium channel gene variant and its effect on channel function, and (2) categorizing clinical phenotype based on functional effect of a variant. The relationship between location, function, and treatment response is also discussed. These interactions can be illustrated by the sodium channelopathies seen in people with epilepsy but generalize beyond that disorder. Ann Neurol 2018;83:1-9.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Location: A surrogate for personalized treatment of sodium channelopathies

Holland

Bouley

Horn

2018

Annals of Neurology

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“…Mutations affecting one SCN4A allele are often associated with a gain-of-function resulting in muscle stiffness (myotonia) that may worsen with repeated contraction (paramyotonia) as well as episodes of hyperkalemic periodic paralysis (1). Phenotypic variability has been reported among family members regarding the age of onset and clinical severity of myotonia (2). Another class of heterozygous SCN4A mutations allow an anomalous leakage of ions through the voltage sensor of the channel, distinct from the sodium-conducting pore, and cause hypokalemic periodic paralysis (3).…”

Section: Introductionmentioning

confidence: 99%

Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L796V Mutation in SCN4A

et al. 2020

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The phenotypic spectrum associated with the skeletal muscle voltage-gated sodium channel gene (SCN4A) has expanded with advancements in genetic testing. Autosomal dominant SCN4A mutations were first linked to hyperkalemic periodic paralysis, then subsequently included paramyotonia congenita, several variants of myotonia, and finally hypokalemic periodic paralysis. Biallelic recessive mutations were later identified in myasthenic myopathy and in infants showing a severe congenital myopathy with hypotonia. We report a patient with a pathogenic de novo SCN4A variant, c.2386C>G p.L796V at a highly conserved leucine. The phenotype was manifest at birth with arthrogryposis multiplex congenita, severe episodes of bronchospasm that responded immediately to carbamazepine therapy, and electromyographic evidence of widespread myotonia. Another de novo case of p.L796V has been reported with hip dysplasia, scoliosis, myopathy, and later paramyotonia. Expression studies of L796V mutant channels showed predominantly gain-of-function changes, that included defects of slow inactivation. Computer simulations of muscle excitability reveal a strong predisposition to myotonia with exceptionally prolonged bursts of discharges, when the L796V defects are included. We propose L796V is a pathogenic variant, that along with other cases in the literature, defines a new dominant SCN4A disorder of myotonic myopathy with secondary congenital joint and skeletal involvement.

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“…1B). Noteworthy, mutations in and around these sites (L689F, I692M, N1151C, A1152C, A1160C, P1158S) impair activation kinetics [39][40][41][42][43][44][45] .…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of voltage-gated sodium channels by peptides mimicking S4-S5 linkers reveals a variation of the ligand-receptor mechanism

Malak

Abderemane-Ali

Wei

et al. 2020

Sci Rep

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prokaryotic na V channels are tetramers and eukaryotic na V channels consist of a single subunit containing four domains. Each monomer/domain contains six transmembrane segments (S1-S6), S1-S4 being the voltage-sensor domain and S5-S6 the pore domain. A crystal structure of Na V Ms, a prokaryotic na V channel, suggests that the S4-S5 linker (S4-S5 L) interacts with the C-terminus of S6 (S6 t) to stabilize the gate in the open state. However, in several voltage-gated potassium channels, using specific S4-S5 L-mimicking peptides, we previously demonstrated that S4-S5 L /S6 t interaction stabilizes the gate in the closed state. Here, we used the same strategy on another prokaryotic Na V channel, Na V Sp1, to test whether equivalent peptides stabilize the channel in the open or closed state. A na V Sp1-specific S4-S5 L peptide, containing the residues supposed to interact with S6 t according to the na V Ms structure, induced both an increase in Na V Sp1 current density and a negative shift in the activation curve, consistent with S4-S5 L stabilizing the open state. Using this approach on a human na V channel, hNa V 1.4, and testing 12 hNa V 1.4 S4-S5 L peptides, we identified four activating S4-S5 L peptides. These results suggest that, in eukaryotic Na V channels, the S4-S5 L of DI, DII and DIII domains allosterically modulate the activation gate and stabilize its open state. Voltage-gated sodium channels (Na V) are crucial in excitable as well as non-excitable cells and mutations in Na V 1.x-subunits have been associated with muscular, neuronal and cardiac channelopathies in human 1. Voltage-gated potassium (K V) channels and prokaryotic Na V channels are tetramers of subunits containing six transmembrane segments (S1 to S6). Each of the four subunits consists of one voltage-sensor domain (S1 to S4) and a pore domain (S5-S6). The four pore domains tetramerize to form a single pore module, which is regulated by the four voltage sensor domains. The arrangement of eukaryotic Na V channels is similar, with one major difference: the channel is made of a single subunit containing four homologous domains, rather than four identical subunits. Each domain in eukaryotic Na V channels is structurally equivalent to one subunit in K V or prokaryotic Na V channels, and consists of six transmembrane segments (S1 to S6). Despite intensive work on the voltage-gating of K V and Na V channels, we still lack a clear picture describing the coupling between S4 voltage-sensor movement and S6 pore gating. Both structural and functional studies identified the linker between S4 and S5 (named S4-S5 L) and the C-terminus of S6 (named S6 T), as major actors in this coupling 2-21. Different coupling mechanisms have been suggested. The crystal structure of K V 1.2, and more recently the cryo-electron microscopy and crystal structures of both eukaryotic and prokaryotic Na V channels suggested that the four S4-S5 L form a mechanical lever or a constriction ring intimately interacting with S6 T when

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Phenotypic Variability in Childhood of Skeletal Muscle Sodium Channelopathies

Cited by 9 publications

References 17 publications

Location: A surrogate for personalized treatment of sodium channelopathies

Location: A surrogate for personalized treatment of sodium channelopathies

Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L796V Mutation in SCN4A

Up-regulation of voltage-gated sodium channels by peptides mimicking S4-S5 linkers reveals a variation of the ligand-receptor mechanism

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