Functional Effects of KCNE3 Mutation and Its Role in the Development of Brugada Syndrome

• DOI: 10.1161/circep.107.748103
• Publication Date: 2008-05-31T01:44:38Z
• Authors: Eva Delpón; Jonathan M. Cordeiro; Lucía Núñez; Poul Erik Bloch T...; Alejandra Guerchi...; Guido D. Pollevick; Yuesheng Wu; J�rgen K. Kanters; Carsten Toftager ...; Jacob Hofman-Bang; Elena Burashnikov; Michael Christiansen; Charles Antzelevitch
• Keywords: Adult; Male; Potassium Channels; Patch-Clamp Techniques; Adolescent; Cells; DNA Mutational Analysis; Mutation, Missense; Action Potentials; Young Adult; 03 medical and health sciences; 0302 clinical medicine; Humans; Immunoprecipitation; Genetic Predisposition to Disease; Child; Cells, Cultured; Aged; Brugada Syndrome; Cultured; Myocardium; Voltage-Gated; DNA; Middle Aged; Pedigree; Mutation; Female; Missense; Follow-Up Studies

The Brugada Syndrome (BrS), an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in four different genes leading loss function sodium and calcium channel activity. Although the transient outward current (I(to)) is thought play prominent role expression syndrome, I(to)-related have not identified as yet.One hundred five probands BrS were screened for ion gene using single strand conformation polymorphism (SSCP) electrophoresis direct sequencing. A missense mutation (R99H) KCNE3 (MiRP2) was detected one proband. R99H found 4/4 phenotype positive 0/3 phenotype-negative family members. Chinese hamster ovary (CHO)-K1 cells co-transfected wild-type (WT) or mutant either WT KCND3 KCNQ1. Whole-cell patch clamp studies performed after 48 hours. Interactions between Kv4.3 analyzed co-immunoprecipitation experiments human atrial samples. Co-transfection R99H-KCNE3 KCNQ1 produced no alteration magnitude kinetics. However, co-transfection resulted significant increase I(to) intensity compared KCNE3+KCND3. Using tissues isolated from left appendages hearts, we also demonstrate that K(v)4.3 can be co-immunoprecipitated.These results provide definitive evidence functional modulation heart suggest underlie development BrS.