Abstract 1970: Genetic Causes Modifiers and Novel Candidates of Long QT Syndrome (LQTS)
Long QT syndrome (LQTS) is a condition associated with prolonged ventricular repolarisation that predisposes individuals to life-threatening arrhythmias. Over 700 different LQTS-causing mutations have been identified in 12 genes. To determine the spectrum of LQTS-causing mutations in South Africa we performed genetic analysis of five of the most frequently implicated LQTS-causing genes in 69 index cases. PCR-SSCP analysis has identified several non-synonymous sequence variants and 19 disease-causing mutations, 4% were compound heterozygotes. A cohort of 23 families, affected by a founder disease-causing mutation (Kv7.1-A341V), was previously identified. We screened several polymorphisms within LQT-causing genes for association with clinical heterogeneity within these founder families. When controlling for the effect of Kv7.1-A341V, both Kv11.1-K897T and Nav1.5-H558R were shown to influence QTc interval length. We also identified putative interactors of the C-terminal of Kv7.1 by yeast two-hybrid (Y2H) analysis. Of the seven interactors identified by Y2H, four (MYL2, ACTN2, PRKAR1A and SYNE1) were considered putative physiological interactors based on the plausibility of the interactions as assessed in silico. MYL2 encodes the regulatory light chain associated with cardiac myosin beta heavy chain. Ca + triggers the phosphorylation of MYL2 which, in turn, triggers contraction. ACTN2 encodes a muscle-specific, alpha actinin isoform which is an actin-binding protein. In muscle, ACTN2 isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. PRKAR1A encodes a regulatory subunit of PKA which plays a role cAMP-dependent phosphorylation of different target proteins including Kv7.1. SYNE1 encodes Nesprin which attaches to cytoskeleton’s actin filaments and to emerin which is found in the inner nuclear membrane. Nesprin has also been localized to the cytoplasm. We have identified a number of disease-causing mutations within the South African LQTS population. Additionally, we have confirmed the QTc altering effects of several non-pathogenic variants. The identification of Kv7.1-interacting proteins provides a number of novel LQTS-causing and -modifying candidates.