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SCN5A  -  sodium channel, voltage gated, type V...

Homo sapiens

Synonyms: CDCD2, CMD1E, CMPD2, HB1, HB2, ...
 
 
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Disease relevance of SCN5A

 

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

 

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

 

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

References

  1. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Wang, Q., Shen, J., Splawski, I., Atkinson, D., Li, Z., Robinson, J.L., Moss, A.J., Towbin, J.A., Keating, M.T. Cell (1995) [Pubmed]
  2. 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. Schwartz, P.J., Priori, S.G., Locati, E.H., Napolitano, C., Cantù, F., Towbin, J.A., Keating, M.T., Hammoude, H., Brown, A.M., Chen, L.S. Circulation (1995) [Pubmed]
  3. Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy. Locke, G.R., Ackerman, M.J., Zinsmeister, A.R., Thapa, P., Farrugia, G. Am. J. Gastroenterol. (2006) [Pubmed]
  4. Inherited arrhythmic disorders in Japan. Hiraoka, M. J. Cardiovasc. Electrophysiol. (2003) [Pubmed]
  5. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Wattanasirichaigoon, D., Vesely, M.R., Duggal, P., Levine, J.C., Blume, E.D., Wolff, G.S., Edwards, S.B., Beggs, A.H. Am. J. Med. Genet. (1999) [Pubmed]
  6. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. Makita, N., Behr, E., Shimizu, W., Horie, M., Sunami, A., Crotti, L., Schulze-Bahr, E., Fukuhara, S., Mochizuki, N., Makiyama, T., Itoh, H., Christiansen, M., McKeown, P., Miyamoto, K., Kamakura, S., Tsutsui, H., Schwartz, P.J., George, A.L., Roden, D.M. J. Clin. Invest. (2008) [Pubmed]
  7. A preliminary study of parental stress and child behaviour in families with twins conceived by in-vitro fertilization. Cook, R., Bradley, S., Golombok, S. Hum. Reprod. (1998) [Pubmed]
  8. The couple's decision-making in IVF: one or two embryos at transfer? Blennborn, M., Nilsson, S., Hillervik, C., Hellberg, D. Hum. Reprod. (2005) [Pubmed]
  9. Psychological status of in vitro fertilization patients during pregnancy: a longitudinal study. Klock, S.C., Greenfeld, D.A. Fertil. Steril. (2000) [Pubmed]
  10. Does psychological stress affect the outcome of in vitro fertilization? Anderheim, L., Holter, H., Bergh, C., Möller, A. Hum. Reprod. (2005) [Pubmed]
  11. Psychological interference in in vitro fertilization treatment. Smeenk, J.M., Verhaak, C.M., Braat, D.D. Fertil. Steril. (2004) [Pubmed]
  12. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. Zareba, W., Moss, A.J., Schwartz, P.J., Vincent, G.M., Robinson, J.L., Priori, S.G., Benhorin, J., Locati, E.H., Towbin, J.A., Keating, M.T., Lehmann, M.H., Hall, W.J. N. Engl. J. Med. (1998) [Pubmed]
  13. A sodium-channel mutation causes isolated cardiac conduction disease. Tan, H.L., Bink-Boelkens, M.T., Bezzina, C.R., Viswanathan, P.C., Beaufort-Krol, G.C., van Tintelen, P.J., van den Berg, M.P., Wilde, A.A., Balser, J.R. Nature (2001) [Pubmed]
  14. New mechanism contributing to drug-induced arrhythmia: rescue of a misprocessed LQT3 mutant. Liu, K., Yang, T., Viswanathan, P.C., Roden, D.M. Circulation (2005) [Pubmed]
  15. Gene-specific therapy for inherited arrhythmogenic diseases. Napolitano, C., Bloise, R., Priori, S.G. Pharmacol. Ther. (2006) [Pubmed]
  16. Accelerated inactivation in a mutant Na(+) channel associated with idiopathic ventricular fibrillation. Wan, X., Chen, S., Sadeghpour, A., Wang, Q., Kirsch, G.E. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  17. Effect of the antimalarial drug halofantrine in the long QT syndrome due to a mutation of the cardiac sodium channel gene SCN5A. Piippo, K., Holmström, S., Swan, H., Viitasalo, M., Raatikka, M., Toivonen, L., Kontula, K. Am. J. Cardiol. (2001) [Pubmed]
  18. Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes. Viswanathan, P.C., Bezzina, C.R., George, A.L., Roden, D.M., Wilde, A.A., Balser, J.R. Circulation (2001) [Pubmed]
  19. Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. Wang, Q., Shen, J., Li, Z., Timothy, K., Vincent, G.M., Priori, S.G., Schwartz, P.J., Keating, M.T. Hum. Mol. Genet. (1995) [Pubmed]
  20. Identification of a new SCN5A mutation, D1840G, associated with the long QT syndrome. Mutations in brief no. 153. Online. Benhorin, J., Goldmit, M., MacCluer, J.W., Blangero, J., Goffen, R., Leibovitch, A., Rahat, A., Wang, Q., Medina, A., Towbin, J., Kerem, B. Hum. Mutat. (1998) [Pubmed]
  21. The long QT syndrome. A review of recent molecular genetic and physiologic discoveries. Keating, M.T. Medicine (Baltimore) (1996) [Pubmed]
  22. Myotonia caused by mutations in the muscle chloride channel gene CLCN1. Pusch, M. Hum. Mutat. (2002) [Pubmed]
  23. Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms. Makita, N., Sasaki, K., Groenewegen, W.A., Yokota, T., Yokoshiki, H., Murakami, T., Tsutsui, H. Heart rhythm : the official journal of the Heart Rhythm Society. (2005) [Pubmed]
  24. Molecular biology of the long QT syndrome: impact on management. Priori, S.G., Napolitano, C., Paganini, V., Cantù, F., Schwartz, P.J. Pacing and clinical electrophysiology : PACE. (1997) [Pubmed]
  25. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. Ackerman, M.J., Siu, B.L., Sturner, W.Q., Tester, D.J., Valdivia, C.R., Makielski, J.C., Towbin, J.A. JAMA (2001) [Pubmed]
  26. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A. J. Biol. Chem. (2004) [Pubmed]
  27. Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and beta1-subunits. An, R.H., Wang, X.L., Kerem, B., Benhorin, J., Medina, A., Goldmit, M., Kass, R.S. Circ. Res. (1998) [Pubmed]
  28. Effects of estradiol on cardiac ion channel currents. Möller, C., Netzer, R. Eur. J. Pharmacol. (2006) [Pubmed]
  29. Genetics, molecular mechanisms and management of long QT syndrome. Wang, Q., Chen, Q., Towbin, J.A. Ann. Med. (1998) [Pubmed]
  30. Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A. Boehmer, C., Wilhelm, V., Palmada, M., Wallisch, S., Henke, G., Brinkmeier, H., Cohen, P., Pieske, B., Lang, F. Cardiovasc. Res. (2003) [Pubmed]
  31. Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3. Weiss, R., Barmada, M.M., Nguyen, T., Seibel, J.S., Cavlovich, D., Kornblit, C.A., Angelilli, A., Villanueva, F., McNamara, D.M., London, B. Circulation (2002) [Pubmed]
  32. Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Mohler, P.J., Rivolta, I., Napolitano, C., LeMaillet, G., Lambert, S., Priori, S.G., Bennett, V. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  33. Cardiac ankyrins: Essential components for development and maintenance of excitable membrane domains in heart. Cunha, S.R., Mohler, P.J. Cardiovasc. Res. (2006) [Pubmed]
  34. Syntrophin gamma 2 regulates SCN5A gating by a PDZ domain-mediated interaction. Ou, Y., Strege, P., Miller, S.M., Makielski, J., Ackerman, M., Gibbons, S.J., Farrugia, G. J. Biol. Chem. (2003) [Pubmed]
  35. State-dependent mibefradil block of Na+ channels. McNulty, M.M., Hanck, D.A. Mol. Pharmacol. (2004) [Pubmed]
  36. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. van Bemmelen, M.X., Rougier, J.S., Gavillet, B., Apothéloz, F., Daidié, D., Tateyama, M., Rivolta, I., Thomas, M.A., Kass, R.S., Staub, O., Abriel, H. Circ. Res. (2004) [Pubmed]
  37. Novel mechanism for sudden infant death syndrome: Persistent late sodium current secondary to mutations in caveolin-3. Cronk, L.B., Ye, B., Kaku, T., Tester, D.J., Vatta, M., Makielski, J.C., Ackerman, M.J. Heart rhythm : the official journal of the Heart Rhythm Society (2007) [Pubmed]
  38. Single nucleotide polymorphism map of five long-QT genes. Aydin, A., Bähring, S., Dahm, S., Guenther, U.P., Uhlmann, R., Busjahn, A., Luft, F.C. J. Mol. Med. (2005) [Pubmed]
  39. Cardiac channelopathies: from men to mice. Charpentier, F., Demolombe, S., Escande, D. Ann. Med. (2004) [Pubmed]
  40. Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels. Anson, B.D., Ackerman, M.J., Tester, D.J., Will, M.L., Delisle, B.P., Anderson, C.L., January, C.T. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  41. Long QT syndrome in children: the value of rate corrected QT interval and DNA analysis as screening tests in the general population. Allan, W.C., Timothy, K., Vincent, G.M., Palomaki, G.E., Neveux, L.M., Haddow, J.E. Journal of medical screening. (2001) [Pubmed]
  42. Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Wang, Q., Li, Z., Shen, J., Keating, M.T. Genomics (1996) [Pubmed]
  43. Tetrodotoxin-resistant Na+ channels in human neuroblastoma cells are encoded by new variants of Nav1.5/SCN5A. Ou, S.W., Kameyama, A., Hao, L.Y., Horiuchi, M., Minobe, E., Wang, W.Y., Makita, N., Kameyama, M. Eur. J. Neurosci. (2005) [Pubmed]
  44. SCN5A is expressed in human jejunal circular smooth muscle cells. Ou, Y., Gibbons, S.J., Miller, S.M., Strege, P.R., Rich, A., Distad, M.A., Ackerman, M.J., Rae, J.L., Szurszewski, J.H., Farrugia, G. Neurogastroenterol. Motil. (2002) [Pubmed]
 
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