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(Circulation. 2007;116:134-142.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

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

Argelia Medeiros-Domingo, MD^*; Toshihiko Kaku, MD, PhD^*; David J. Tester, BS; Pedro Iturralde-Torres, MD; Ajit Itty, MD; Bin Ye, PhD; Carmen Valdivia, MD; Kazuo Ueda, MD, PhD; Samuel Canizales-Quinteros, PhD; Maria Teresa Tusié-Luna, MD, PhD; Jonathan C. Makielski, MD; Michael J. Ackerman, MD, PhD

From the Instituto de Investigaciones Biomédicas (A.M.-D., S.C.-Q., M.T.T.-L.), Universidad Nacional Autónoma de México; the Instituto Nacional de Ciencias Médicas y Nutrición (A.M.-D., S.C.-Q., M.T.T.-L.), Salvador Zubirán, México; the Departments of Medicine and Physiology (T.K., B.Y., C.V., K.U., J.C.M.), University of Wisconsin, Madison.; the Mayo Medical School (A.I., M.J.A.), the Department of Molecular Pharmacology and Experimental Therapeutics (A.M.-D., D.J.T., M.J.A.), the Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), and the Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic College of Medicine, Rochester, Minn.; the Instituto Nacional de Cardiología (P.I.-T.), Ignacio Chávez, México.

Correspondence to Michael J. Ackerman, MD, PhD, Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic College of Medicine, Rochester, MN 55905. E-mail ackerman.michael{at}mayo.edu

Received August 17, 2006; accepted April 20, 2007.

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 β-subunits. Four different β-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_vβ-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_V1.5). Compared with the wild-type, L179F-β4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-β4) 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_vβ4 as a novel LQT3-susceptibility gene.

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