Question

1) What is the molecular basis of the Long Q-T syndrome disease? (What is abnormal at the cellular, biochemical, or molecular level?

2) What is the genetic basis of Long Q-T syndrome?

Answer 1

QT syndrome is an inherited genetic disease characterised by irregular heart beats primarily due to improper repolarization potential in heart muscles. ECG of a typical QT patient shows longer QT intervals. Hence, congenital long QT Syndrome is considered fatal , it's an arrhythmic cardiac Syndrome.

Genetic determinants of LQTS are mutations in the ion gated channels (Na+-K+) pump proteins. Mutations in these proteins lead to improper transmembrane proteins whose structure is compromised. Mutations that account for >90% of LQTS are seen in KCNQ1, KCNH2 and SCNA5 genes. These genes encode proteins which conduct outward potassium currents during platue phase of cardiac action potential, there by acheiving cardiac repolarization. Therefore, mutations in the genes lead to loss of function/ improper ion gate function.

Cardiac repolarization occurs in two distinct phases , active phase I_kr and I_ks corresponding to rapid and slow rectifier current in Purkinje muscles. LQTS associate protiens are involved delayed rectifier potassium currents.

Congenital autosomal recessive Romano ward syndrome and Jervell and autosomal dominant Lange-Nielsen syndrome ( hearing loss is seen in these patients) are loss of functions in KCNQ1. Where as gain of function in sodium channel SCN5A also gives LQTS Phenotype.