19^th Annual Cardiology Conference (10 Plenary Forums - 1 Event)

Biography

Biography: Bi-Hua Tan

Abstract

The gene SCN5A on chromosome 3 encodes the α-subunit of the voltage-gated cardiac sodium channel (hNav1.5) that is responsible for large peak inward sodium current (I_Na) and late I_Na.  Peak I_Na underlies excitability and conduction in working myocardium (atrial and ventricular cells) and special conduction tissues (Purkinje cells etc.). Late I_Na influences repolarization and refractoriness. The importance of I_Na for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired Na channel diseases. SCN5A in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. Common sequence variants ("polymorphisms") have also been implicated as risk factors in multiple diseases. Mutations in the cardiac Na channel gene SCN5A cause loss-of-function or gain-of-function and underlie arrhythmia syndromes, such as Brugada syndrome, cardiac conduction disorder, congenital sick sinus syndrome, idiopathic ventricular fibrillation, sudden infant death syndrome, the type 3 long QT syndrome etc. Here, 3 unrelated inherited arrhythmia cases will be presented to show that the loss-of-function or gain-of-function biophysical phenotypes for sodium channel mutations depend on the splice variant background in which it is expressed and the intracellular acidosis, and is also modulated by common polymorphism.

Recent Publications

1. Hu RM*, Tan BH*, Tester DJ, Song C, He Y, Dovat S, Peterson BZ, Acherman MJ, Makielski JC (2015) Arrhythmogenic biophysical phenotype for SCN5A mutation S1787N depends upon splice variant background and intracellular acidosis. PLoS ONE. Apr 29: 10(4):e0124921. doi: 10.1371/journal.pone.0124921. eCollection
2. Hu RM, Tan BH, Orland KM, Valdivia CR, Peterson A, Pu J, Makielski JC (2013) Digenic inheritance novel mutations in SCN5a and SNTA1 increase late INa contributing to LQT syndrome. Am J Physiol Heart Circ Physiol. Apr: 304(7):H994-H1001.
3. Tester DJ*, Tan BH*, Medeiros-Domingo A, Song C, Makielski JC, Ackerman MJ (2011) Loss-of-Function Mutations in the KCNJ8-Encoded Kir6.1 K_ATP Channel and Sudden Infant Death Syndrome. Circ Cardiovasc Genet. 4:510-515.
4. Medeiros-Domingo A*, Tan BH*, Crotti L*, Tester DJ, Eckhardt LL, Cuoretti A, Kroboth SL, Song C, Zhou Q, Kopp D, Schwartz PJ, Makielski JC, Ackerman MJ (2010) Gain-of-Function Mutation, S422L, in the KCNJ8-Encoded Cardiac K_ATP Channel Kir6.1 as a Pathogenic Substrate for J Wave Syndromes. Heart Rhythm. 7:1466-1471.
5. Tan BH, Pundi KN, Van Norstrand DW, Valdivia CR, Tester DJ, Medeiros-Domingo A, Makielski JC. Ackerman MJ (2010)

Sudden Infant Death Syndrome-Associated Mutations in the Sodium Channel Beta Subunits. Heart Rhythm. 7(6):771-778.

6. Medeiros-Domingo A*, Tan BH*, Iturralde-Torres P, Tester DJ, Tusié-Luna T, Makielski JC. Ackerman MJ (2009) Unique mixed phenotype and unexpected functional Effect revealed by novel compound heterozygosity mutations involving SCN5A. Heart Rhythm. 6(8):1170-1175.
7. Tan BH, Iturralde-Torres P, Medeiros-Domingo A, Nava S, Tester DJ, Valdivia CR, Tusié-Luna T, Ackerman MJ, Makielski JC (2007) A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia. Cardiovascular Research. 76:409-417.
8. Tan BH, Valdivia CR, Song C, Makielski JC (2006). Partial expression defect for the SCN5A missense mutation G1406R depends upon splice variant background Q1077 and rescue by mexiletine. Am J Physiol Heart Circ Physiol.  291: H1822- H1828.
9. Tan BH,, Valdivia CR, Rok BA, Ye B,  Ruwaldt KM, Tester DJ,  Ackerman MJ, Makielski JC (2005) Common human SCN5A polymorphisms have altered electrophysiology when expressed in the Q1077 splice variants.  Heart Rhythm.  2(7): 741-747.