Disease relevance of SCN5A

• SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome [1].
• Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy [2].
• Fifty percent of the subjects with an SCN5A mutation reported abdominal pain compared to only 13% of controls (OR 5.7; 95% CI 1.3-24.4) [3].
• A case of idiopathic ventricular fibrillation was found to have a novel mutation in SCN5A, in which the expressed current showed marked suppression of channel function [4].
• We have examined the SCN5A gene in 88 index cases with LQTS, including four with Jervell and Lange-Nielsen syndrome and the remainder with Romano-Ward syndrome [5].
• Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction [6].

Psychiatry related information on SCN5A

• However, parents whose children were conceived by IVF reported greater stress associated with parenting than parents with naturally conceived twins [7].
• The couple's decision-making in IVF: one or two embryos at transfer [8]?
• The IVF group, not controls, reported improved self-esteem and decreased anxiety as the pregnancy progressed [9].
• CONCLUSIONS: We found no evidence that psychological stress had any influence on the outcome of IVF treatment [10].
• Because several studies indicate that psychological factors play a role in dropping out of IVF treatment, the question arises as to whether psychological interference is indicated [11].

High impact information on SCN5A

• METHODS: We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus [12].
• RESULTS: The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (P<0.001 for the comparison of all three groups) [12].
• Although cumulative mortality is similar regardless of the genotype, the percentage of cardiac events that are lethal is significantly higher in families with mutations at the LQT3 locus [12].
• Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene [1].
• By analysing the SCN5A coding region, we have identified a single mutation in five affected family members; this mutation results in the substitution of cysteine 514 for glycine (G514C) in the channel protein [13].

Chemical compound and disease context of SCN5A

• BACKGROUND: The cardiac sodium channel (SCN5A) mutation L1825P has been identified in a patient with drug-induced torsade de pointes precipitated by the IKr blocker cisapride [14].
• The first attempt for a gene-specific therapy was made in 1995 with the use of mexiletine in long-QT syndrome (LQTS) patients with mutations in the SCN5A gene [15].
• A missense mutation of SCN5A that substitutes glutamine for leucine at codon 567 (L567Q, in the cytoplasmic linker between domains I and II) is identified with sudden infant death and Brugada syndrome in one family [16].
• Effect of the antimalarial drug halofantrine in the long QT syndrome due to a mutation of the cardiac sodium channel gene SCN5A [17].
• Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes [18].

Biological context of SCN5A

• These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder [1].
• Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families [1].
• We used single-strand conformation polymorphism (SSCP) and DNA sequence analyses to identify mutations in the cardiac sodium channel gene, SCN5A, in affected members of four LQT families [19].
• We identified a new point-mutation, A to G substitution at nucleotide 5519 of the SCN5A gene, changing the aspartate 1840 to glycine, D1840G [20].
• We used molecular genetics to identify genes responsible for 2 forms of LQT (cardiac potassium and sodium channel genes HERG and SCN5A, respectively) [21].

Anatomical context of SCN5A

• Pure non-syndromic, non-dystrophic myotonia in humans is caused by mutations in the genes coding for the skeletal muscle sodium channel (SCN5A) or the skeletal muscle chloride channel (CLCN1) with similar phenotypes [22].
• Incomplete penetrance observed in atrial standstill has been attributed in part to the digenic inheritance of polymorphisms in the atrial-specific gap junction connexin 40 (Cx40) in conjunction with an SCN5A mutation [23].
• Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively [24].
• Genomic DNA was extracted from frozen myocardium and subjected to SCN5A mutational analyses [25].
• On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance [26].

Associations of SCN5A with chemical compounds

• The mutation, a single A-->G base substitution at nucleotide 5519 of the SCN5A cDNA, is expected to cause a nonconservative change from an aspartate to a glycine at position 1790 (D1790G) of the SCN5A gene product [27].
• The HERG-mediated potassium and the SCN5A-mediated sodium currents, however, were only slightly reduced by estradiol at concentrations of up to 30 muM [28].
• Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCN5A mutations [29].
• Opposite shifts of gating properties were elicited by mutation of serine to alanine (S483ASCN5A and S663ASCN5A) in the SGK consensus sequences of SCN5A [30].
• CONCLUSIONS: A Brugada syndrome locus distinct from SCN5A is associated with progressive conduction disease, a low sensitivity to procainamide testing, and a relatively good prognosis in a single large pedigree [31].

Physical interactions of SCN5A

• Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes [32].

Regulatory relationships of SCN5A

• Human variants in SCN5A (encodes Na(v)1.5) that block Na(v)1.5 interaction with ankyrin-G lead to loss of Na(v)1.5 membrane expression and Brugada syndrome [33].
• Syntrophin gamma 2 regulates SCN5A gating by a PDZ domain-mediated interaction [34].
• 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 [35].
• Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination [36].
• CAV3 mutations were engineered using site-directed mutagenesis and heterologously expressed in HEK293 cell lines stably expressing the SCN5A-encoded cardiac sodium channel [37].

Other interactions of SCN5A

• Four SNPs were associated with QTc interval in our 141 subjects, one in KCNE1, one in KCNE2, and two in SCN5A [38].
• Among these LQT models, the LQT3 and LQT4 mice exhibit spontaneous or exercise-induced life-threatening arrhythmias characteristics of long-QT patients [39].
• However, the identification of common nonsynonymous single nucleotide polymorphisms (nSNPs; i.e., amino-acid coding variants) with functional phenotypes in the SCN5A Na(+) channel and MiRP1 K(+) channel beta-subunit have challenged this viewpoint [40].
• Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms [23].
• BACKGROUND: Congenital atrial standstill has been linked to SCN5A [23].

Analytical, diagnostic and therapeutic context of SCN5A

• METHODS: Families with KVLQT1, HERG, or SCN5A genotypes provided electrocardiographic (ECG) data for this analysis [41].
• Biophysical properties of the wild-type (WT) and mutant SCN5A channels in a heterologous expression system were studied using the whole-cell patch clamp technique [23].
• Oligonucleotide primers based on exon-flanking sequences amplify all SCN5A exons by PCR [42].
• Sequence analysis has indicated that hNbR1 is highly homologous with human cardiac Nav1.5/SCN5A with > 99% amino acid identity [43].
• RT-PCR on the harvested cells showed that SCN5A was present in circular but not in longitudinal muscle [44].

References