A missense mutation (R99H) in KCNE3 was identified in a Brugada syndrome proband, which significantly increased Ito intensity compared with wild-type KCNE3, suggesting its role in the syndrome.
Observational (n=105)
Does the R99H mutation in KCNE3 alter Ito intensity and contribute to the development of Brugada syndrome?
The R99H mutation in KCNE3 significantly increases Ito intensity, providing evidence for its functional role in the development of Brugada syndrome.
Background— The Brugada syndrome, an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in 4 different genes, leading to a loss of function in sodium and calcium channel activity. Although the transient outward current ( I to ) is thought to play a prominent role in the expression of the syndrome, mutations in I to -related genes have not been identified as yet. Methods and Results— One hundred five probands with the Brugada syndrome were screened for ion channel gene mutations using single-strand conformation polymorphism electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 ( MiRP2 ) was detected in 1 proband. The R99H mutation was found 4/4 phenotype-positive and 0/3 phenotype-negative family members. Chinese hamster ovary-K1 cells were cotransfected using wild-type (WT) or mutant KCNE3 and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and KCNE3 were analyzed in coimmunoprecipitation experiments in human atrial samples. Cotransfection of R99H- KCNE3 with KCNQ1 produced no alteration in tail current magnitude or kinetics. However, cotransfection of R99H KCNE3 with KCND3 resulted in a significant increase in the I to intensity compared with WT KCNE3 +KCND3. Using tissues isolated from the left atrial appendages of human hearts, we also demonstrate that K v 4.3 and KCNE3 can be coimmunoprecipitated. Conclusions— These results provide definitive evidence for a functional role of KCNE3 in the modulation of I to in the human heart and suggest that mutations in KCNE3 can underlie the development of the Brugada syndrome.
Delpón et al. (Sat,) conducted a observational in Brugada syndrome (n=105). KCNE3 mutation (R99H) screening and functional analysis vs. Wild-type KCNE3 was evaluated on Identification of ion channel gene mutations and functional alteration in Ito intensity. A missense mutation (R99H) in KCNE3 was identified in a Brugada syndrome proband, which significantly increased Ito intensity compared with wild-type KCNE3, suggesting its role in the syndrome.