6agf

Structural highlights

Disease

[SCN4A_HUMAN] Postsynaptic congenital myasthenic syndromes;Paramyotonia congenita of Von Eulenburg;Myotonia fluctuans;Hyperkalemic periodic paralysis;Acetazolamide-responsive myotonia;Myotonia permanens;Hypokalemic periodic paralysis. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. SCN4A mutations are the cause of an autosomal recessive neuromuscular disorder characterized by severe fetal hypokinesia, neonatal hypotonia and congenital myopathy of variable severity. The most severe clinical features include reduced or absent fetal movements, in-utero upper and lower limb contractures, talipes and hydrops, and intrauterine or early postnatal death. Mildly affected patients present with generalized hypotonia and weakness at birth or within the first few days of life, mild-to-moderate facial muscle weakness without ptosis, significant early respiratory and feeding difficulties, and skeletal abnormalities of the spine and palate. Symptoms improve over time in patients who survive infancy, resulting in gain of muscle strength and motor skills and concomitant resolution of early respiratory and feeding difficulties. In contrast to other SCN4A-related channelopathies, affected individuals manifest in-utero or neonatal onset of permanent muscle weakness, rather than later-onset episodic muscle weakness.^[1] [SCN1B_HUMAN] Dravet syndrome;Familial progressive cardiac conduction defect;Generalized epilepsy with febrile seizures-plus;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry. The gene represented in this entry may be involved in disease pathogenesis. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

[SCN4A_HUMAN] This 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, the protein 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.^{[2] [3]} [SCN1B_HUMAN] Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-1 can modulate multiple alpha subunit isoforms from brain, skeletal muscle, and heart. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons.^[4] Isoform 2: Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth.^[5]

References

1. ↑ Zaharieva IT, Thor MG, Oates EC, van Karnebeek C, Hendson G, Blom E, Witting N, Rasmussen M, Gabbett MT, Ravenscroft G, Sframeli M, Suetterlin K, Sarkozy A, D'Argenzio L, Hartley L, Matthews E, Pitt M, Vissing J, Ballegaard M, Krarup C, Slordahl A, Halvorsen H, Ye XC, Zhang LH, Lokken N, Werlauff U, Abdelsayed M, Davis MR, Feng L, Phadke R, Sewry CA, Morgan JE, Laing NG, Vallance H, Ruben P, Hanna MG, Lewis S, Kamsteeg EJ, Mannikko R, Muntoni F. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy. Brain. 2016 Mar;139(Pt 3):674-91. doi: 10.1093/brain/awv352. Epub 2015 Dec 22. PMID:26700687 doi:http://dx.doi.org/10.1093/brain/awv352
2. ↑ Dice MS, Abbruzzese JL, Wheeler JT, Groome JR, Fujimoto E, Ruben PC. Temperature-sensitive defects in paramyotonia congenita mutants R1448C and T1313M. Muscle Nerve. 2004 Sep;30(3):277-88. doi: 10.1002/mus.20080. PMID:15318338 doi:http://dx.doi.org/10.1002/mus.20080
3. ↑ Carle T, Lhuillier L, Luce S, Sternberg D, Devuyst O, Fontaine B, Tabti N. Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis. Biochem Biophys Res Commun. 2006 Sep 22;348(2):653-61. doi:, 10.1016/j.bbrc.2006.07.101. Epub 2006 Jul 28. PMID:16890191 doi:http://dx.doi.org/10.1016/j.bbrc.2006.07.101
4. ↑ Qin N, D'Andrea MR, Lubin ML, Shafaee N, Codd EE, Correa AM. Molecular cloning and functional expression of the human sodium channel beta1B subunit, a novel splicing variant of the beta1 subunit. Eur J Biochem. 2003 Dec;270(23):4762-70. PMID:14622265
5. ↑ Qin N, D'Andrea MR, Lubin ML, Shafaee N, Codd EE, Correa AM. Molecular cloning and functional expression of the human sodium channel beta1B subunit, a novel splicing variant of the beta1 subunit. Eur J Biochem. 2003 Dec;270(23):4762-70. PMID:14622265
6. ↑ Pan X, Li Z, Zhou Q, Shen H, Wu K, Huang X, Chen J, Zhang J, Zhu X, Lei J, Xiong W, Gong H, Xiao B, Yan N. Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1. Science. 2018 Sep 6. pii: science.aau2486. doi: 10.1126/science.aau2486. PMID:30190309 doi:http://dx.doi.org/10.1126/science.aau2486