Disease relevance of SCN4A

• Functional expression of the SCN1B and one of the SCN1A mutations revealed defects in fast channel inactivation which are in line with previous findings on myotonia causing mutations in SCN4A, the skeletal muscle sodium channel alpha-subunit gene, all showing an impaired fast inactivation [1].
• Mutation screening in Korean hypokalemic periodic paralysis patients: a novel SCN4A Arg672Cys mutation [2].
• Mutations in the skeletal muscle sodium channel gene (SCN4A) have been described in paramyotonia congenita (PMC) and hyperkalaemic periodic paralysis (HPP) [3].
• DNA from seven unrelated patients with hyperkalemic periodic paralysis (HYPP) was examined for mutations in the adult skeletal muscle sodium channel gene (SCN4A) known to be genetically linked to the disorder [4].
• Mutations in the skeletal muscle voltage-gated sodium channel alpha-subunit gene (SCN4A) have been associated with a spectrum of inherited nondystrophic myotonias and periodic paralyses [5].

High impact information on SCN4A

• Paramyotonia congenita (PMC), a dominant disorder featuring cold-induced myotonia (muscle stiffness), has recently been genetically linked to a candidate gene, the skeletal muscle sodium channel gene SCN4A [6].
• Mutations in SCN4A can produce a broad range of phenotypes in muscle diseases characterized by episodic abnormalities of membrane excitability [3].
• Splicing of the AT-AC intron 2 of a sodium channel (SCN4A) precursor messenger RNA in vitro did not require inhibition of conventional splicing and required adenosine triphosphate, magnesium, and U12 small nuclear RNA (snRNA) [7].
• Pursuing this clue, we sequenced SCN4A encoding the skeletal muscle sodium channel (Nav1.4) and detected two heteroallelic mutations involving conserved residues not present in 400 normal alleles: S246L in the S4/S5 cytoplasmic linker in domain I, and V1442E in the S3/S4 extracellular linker in domain IV [8].
• Dinucleotide repeat polymorphisms at the SCN4A locus suggest allelic heterogeneity of hyperkalemic periodic paralysis and paramyotonia congenita [9].

Chemical compound and disease context of SCN4A

• An unusual form of painful congenital myotonia is associated with a novel SCN4A mutation causing a valine to methionine substitution in the domain 1/S6 segment of the skeletal muscle sodium channel [10].
• RESULTS: A three-generation Italian family with myotonia is presented, in which a novel SCN4A mutation (leucine 266 substituted by valine, L266V) is identified [11].
• RESULTS: Four individuals with myotonia were shown to carry a guanine-to-cytosine mutation at nucleotide position 3917 of the reported SCN4A sequence [12].
• SCN4A-associated hypokalemic periodic paralysis merits a trial of acetazolamide [13].
• Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (HypoPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated recently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999) [14].

Biological context of SCN4A

• However, MH has been shown to be genetically heterogeneous, and in the ensuing search for other MHS genes, a locus on chromosome 17q has been proposed, and the gene for the adult muscle sodium channel (SCN4A) was suggested as a candidate [15].
• One family harbored a new heterozygous point mutation C2014A in exon 12 (R672S) of SCN4A [16].
• Restriction mapping and hybridization analysis of YAC and cosmid clones confirmed the close linkage of the CD79b gene to the hGH gene cluster and facilitated the assembly of a 100-kb physical map linking the hGH locus, the CD79b gene, and the more distant muscle-specific sodium channel alpha-subunit (SCN4A) gene [17].
• Reported herein are two Korean hypokalemic periodic paralysis families, one carrying a novel SCN4A Arg672Cys mutation with incomplete penetrance in women, and the other carrying a CACNL1A3 Arg528His mutation, with the onset of characteristics of hypoPP developing at an earlier age, as well as a higher penetrance rate in women [2].
• In the human and rat genomes, the B29 gene is located between the skeletal muscle-specific Na-channel alpha subunit (SCN4A) gene and the pituitary-specific growth hormone (GH-N) gene [18].

Anatomical context of SCN4A

• The authors screened the skeletal muscle sodium channel gene (SCN4A) in the remainder [16].
• In contrast to other disease-causing mutations in SCN1A, SCN1B and SCN4A, the only mechanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation [1].
• Interestingly, intron 21 of the same SCN4A gene and the corresponding intron 25 of the SCN5A cardiac muscle sodium channel gene also have 5'-AT and AC-3' boundaries, but they have divergent 5' splice site and presumptive branch site sequences [19].
• Specific hSkM1 RNA transcripts are expressed in adult human skeletal muscle but not in heart, brain, or uterus [20].
• We used the macropatch technique on Xenopus oocytes to study hSkM1 and hH1 slow inactivation with and without beta(1)-subunit coexpression [21].

Associations of SCN4A with chemical compounds

• A novel SCN4A mutation causing the replacement of Val445 in the sixth transmembrane segment of domain 1 with methionine was discovered in all affected individuals and is the likely genetic basis for the syndrome [5].
• Some remarkable clinical features were observed in a large hypoPP family carrying an SCN4A mutation: a complete penetrance in men and women, an early age at onset, postcritic myalgias and an increased number and severity of attacks induced by acetazolamide [22].
• CONCLUSIONS: The current report provides direct evidence that succinylcholine-induced MMR, whole-body rigidity, and an abnormal IVCT result are associated with a mutation in the SCN4A gene [12].
• Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A) [23].
• All affected family members carried the threonine to methionine substitution at codon 704 (T704M) in exon 13 of the skeletal muscle voltage gated sodium channel gene (SCN4A) [24].

Regulatory relationships of SCN4A

• When selectively applied to channels after inducing slow inactivation with a 60-s pulse to -10 mV, mibefradil (1 microM) produced 45% fractional block in Nav1.5 and greater block (88%) in an isoform (Nav1.4) that slow-inactivates more completely [25].

Other interactions of SCN4A

• Our results exclude the alpha 1, beta 1, and gamma subunit of the DHP receptor as well as the SCN4A locus as candidates for the molecular defect in MHS for these pedigrees where also the RYR1 on chromosome 19q13.1 has been excluded [15].
• We now studied the second GEFS+ mutation (T875M in SCN1A), using the highly homologous SCN4A gene (mutation T685M) [1].
• The authors conclude that SCN4A mutations are an uncommon cause of hypoPP in this UK population [16].
• Our results exclude the alpha 1, beta 1 and gamma subunit of the DHP receptor as well as the SCN4A locus from that region [15].
• Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel (CLCN1) gene, and the muscle sodium channel (SCN4A) gene, was assessed and excluded [26].

Analytical, diagnostic and therapeutic context of SCN4A

• In 15 patients with THypoKPP, using target-exon PCR, CSGE screening, and direct sequencing, we excluded known mutations in CACN1AS and SCN4A genes [27].
• Direct sequence analysis of the SCN4A gene on chromosome 17q, was performed on the proband's DNA [28].
• While SkM1 mRNA levels were relatively unaffected by denervation or steroid treatment, SkM2 mRNA levels were increased by both [29].
• 4. In the animal model of CIM the Nav1.5 sodium channel isoform is upregulated, but the majority of sodium current is still carried by Nav1.4 sodium channels [30].
• Deltamethrin at 10 microM elicited weak gating changes in rat skeletal muscle alpha-subunit Na(+) channels (Nav1.4) after > 30 min of perfusion [31].

References