SCN4B -Encoded Sodium Channel β4 Subunit in Congenital Long-QT Syndrome

Abstract

Background-Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming ␣-subunit associated with 1 or more auxiliary ␤-subunits. Four different ␤-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. Methods and Results-We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Na v␤ -subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel ␣-subunit (hNa V 1.5). Compared with the wild-type, L179F-␤4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A ϩ WT-␤4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. Conclusions-We provide the seminal report of SCN4B-encoded Na v␤ 4 as a novel LQT3-susceptibility gene. (Circulation.

Genetics of Long QT Syndrome

“…the sCn4B-encoded β4 subunit was implicated in lQts with the identification of an l179f mutation in a 21-month-old female with intermittent 2:1 atrioventricular block and extreme Qt prolongation (Qtc, 712 ms). 28 Coexpression of the l179f-sCn4B mutation with wild-type sCn5a led to a significant increase in persistent late sodium current consistent with an lQt3-like electrophysiological phenotype. however, subsequent mutation analysis of sCn4B in a cohort of 262 unrelated genotype-negative lQts patients failed to identify any additional mutations.…”

Clinical Impact of Genetic Studies in Lethal Inherited Cardiac Arrhythmias

“…Since the first 2 genes responsible for LQTS were identified in 1995, 21,22 molecular genetic studies have revealed 12 forms of Romano-Ward-type congenital LQTS caused by mutations in the genes of the potassium, sodium and calcium channels or the membrane adapter located on chromosomes 3, 4, 7, 11, 12, 17, 20 and 21 (Table2). [23][24][25][26][27][28][29][30][31] Mutations in KCNQ1 and KCNE1, the and subunits of the potassium channel gene, are responsible for defects (loss of function) in the slowly activating component of the delayed rectifier potassium current (IKs) underlying the LQT1 and LQT5 forms of LQTS. 32,33 Mutations in KCNH2 and KCNE2 cause defects in the rapidly activating component of the delayed rectifier potassium current (IKr), which is responsible for the LQT2 and LQT6 forms.…”

Pharmacological approach to the treatment of long and short QT syndromes

“…The newer more detailed classification scheme is based on the genetic mutation involved. Ten forms of congenital LQTS have been identified due to mutations in genes encoding for potassium channels, sodium channels or membrane components located on chromosome 3, 4, 6, 7, 11, 17 and 21 (Table 1) (Andersen et al, 1971;Tawil et al, 1994;Splawski et al, 2000;Plaster et al, 2001;Mohler et al, 2003;Splawski et al, 2004;Vatta et al, 2006;Medeiros-Domingo et al, 2007).…”

“…Patient with LQT7 generally shows normal or near normal QT interval and the U waves are usually prominent and separated from the T wave (Mohler et al, 2003). Recently reported LQT10 appears to be associated with extremely long QT interval (>600 ms), fetal bradycardia and atrio-ventricular block (Medeiros-Domingo et al, 2007).…”