SCN4ANav1.4

Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na+ ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues. Highly expressed in skeletal muscles, Nav1.4 generates the action potential crucial for muscle contraction

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Na(+)(in) = Na(+)(out)

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The Nav1.4 voltage-gated sodium channel consists of an ion-conducting alpha subunit SCN4A which is functional on its own and a regulatory beta subunit SCN1B. SCN1B strongly enhances the presence of SCN4A at the cell surface. SCN1B is also required for rapid channel inactivation and recovery after inactivation. It prevents the decrease of channel activity in response to repetitive, high-frequency depolarizations (By similarity). Interacts with the syntrophins SNTA1, SNTB1 and SNTB2 (via PDZ domain); probably links SCN4A to the actin cytoskeleton and the extracellular matrix via the dystrophin-associated protein complex and regulates its localization in muscle cells (By similarity). Interacts with TMEM233; probable regulator of the channel (By similarity)

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Cell membrane / Multi-pass membrane protein

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Paramyotonia congenita PMC An autosomal dominant channelopathy characterized by myotonia, increased by exposure to cold, intermittent flaccid paresis, not necessarily dependent on cold or myotonia, lability of serum potassium, non-progressive nature and lack of atrophy or hypertrophy of muscles. In some patients, myotonia is not increased by cold exposure (paramyotonia without cold paralysis). Patients may have a combination phenotype of PMC and HYPP. The disease is caused by variants affecting the gene represented in this entry MIM: 168300

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Periodic paralysis hypokalemic 2 HOKPP2 An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. The disease is caused by variants affecting the gene represented in this entry MIM: 613345

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Periodic paralysis hyperkalemic HYPP An autosomal dominant channelopathy characterized by episodic flaccid generalized muscle weakness associated with high levels of serum potassium. Concurrence of myotonia is found in HYPP patients. The disease is caused by variants affecting the gene represented in this entry MIM: 170500

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Periodic paralysis normokalemic NKPP A disorder closely related to hyperkalemic periodic paralysis, but marked by a lack of alterations in potassium levels during attacks of muscle weakness. The disease is caused by variants affecting the gene represented in this entry MIM: 170500

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Myotonia SCN4A-related MYOSCN4A A phenotypically highly variable myotonia aggravated by potassium loading, and sometimes by cold. Myotonia is characterized by sustained muscle tensing that prevents muscles from relaxing normally. It causes muscle stiffness that can interfere with movement. In some people the stiffness is very mild, while in other cases it may be severe enough to interfere with walking, running, and other activities of daily life. Myotonia SCN4A-related includes myotonia permanens and myotonia fluctuans. In myotonia permanens, the myotonia is generalized and there is a hypertrophy of the muscle, particularly in the neck and the shoulder. Attacks of severe muscle stiffness of the thoracic muscles may be life threatening due to impaired ventilation. In myotonia fluctuans, the muscle stiffness may fluctuate from day to day, provoked by exercise. The disease is caused by variants affecting the gene represented in this entry MIM: 608390

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Myasthenic syndrome, congenital, 16 CMS16 A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS16 is characterized by fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth. The fatigable weakness involves lid-elevator, external ocular, facial, limb and truncal muscles and an decremental response of the compound muscle action potential on repetitive stimulation. The disease is caused by variants affecting the gene represented in this entry MIM: 614198

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Congenital myopathy 22A, classic CMYO22A A form of congenital myopathy, a clinically and genetically heterogeneous group of muscle disorders characterized by hypotonia and muscle weakness apparent at birth, and specific pathological features on muscle biopsy. CMYO22A is an autosomal recessive form characterized by fetal hypokinesia, polyhydramnios, and severe neonatal hypotonia associated with respiratory insufficiency. Affected individuals who survive the neonatal period have delayed motor development, difficulty walking, proximal muscle weakness of the upper and lower limbs, facial and neck muscle weakness, easy fatigability, and mild limb contractures or foot deformities. The disease is caused by variants affecting the gene represented in this entry MIM: 620351

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Congenital myopathy 22B, severe fetal CMYO22B A severe congenital myopathy, a clinically and genetically heterogeneous group of muscle disorders characterized by hypotonia and muscle weakness apparent at birth, and specific pathological features on muscle biopsy. CMYO22B is an autosomal recessive form characterized by onset in utero. Affected individuals show fetal akinesia, and develop fetal hydrops with pulmonary hypoplasia, severe joint contractures, and generalized muscle hypoplasia. Death occurs in utero or soon after birth. The disease is caused by variants affecting the gene represented in this entry MIM: 620369

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