The skeletal muscle sodium channel gene SCN4A is located on chromosome 17q23-25. It encodes the pore-forming α-subunit of the voltage-gated sodium channel expressed in skeletal muscle, known as sodium channel protein type 4 subunit alpha. The α-subunit consists of 4 homologous domains (DI-DIV), and each domain possesses six hydrophobic putative transmembrane helices (S1-S6). The majority of causative SCN4A mutations are missense, and gain of function mutations are usually located within the pore-forming segments S5-S6, the voltage sensor segment S4 or the S4-S5 linker of the SCN4A channel.
|Basic Information of SCN4A|
|Protein Name||Sodium channel protein type 4 subunit alpha|
|Aliases||SkM1, Sodium channel protein skeletal muscle subunit alpha, Sodium channel protein type IV subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.4|
|Organism||Homo sapiens (Human)|
This SCN4A membrane protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, SCN4A forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle. Mutations that decrease Na+ channel function generally lead to periodic paralysis phenotypes, while increased channel activity, or non-inactivated channels, result in non-dystrophic myotonia phenotypes. Mutations in SCN4A are associated with various neuromuscular disorders that are labeled collectively as skeletal muscle sodium channelopathy. These disorders include hyperkalemic periodic paralysis, hypokalemic periodic paralysis type 2, paramyotonia congenital, sodium channel myotonias and congenital myasthenic syndrome.
Fig.1 Scheme of skeletal muscle sodium channel Nav1.4 encoded by SCN4A and the identified mutations. (Tsujino, 2003)
This article finds that mutations in CACNA1S and SCN4A are relatively rare in Chinese HPP cases compared with cases in Western individuals.
This article suggests that the single nucleotide polymorphisms in SCN4A gene play a role in Iranian patients with non-dystrophic myotonias.
This article provides guidance for diagnosis by summarizing clinical features of the 2 mutations and establishes the genotype-phenotype correlations.
This article reveals that SCN4A mutations may be an enhancer of the myotonic dystrophy type 2 phenotype. Further screening of SCN4A in DM2 cases with atypical myotonic phenotype is likely to reveal other cases in the future.
This article suggests that mutations in SCN4A should be considered as differential diagnosis of recurrent life-threatening laryngospasm infantile.
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