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

Abstract

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.

Brugada syndrome: clinical and genetic findings

“…A functional role for the MinK-related peptide 2 (MiRP2) protein, encoded by KCNE3, in the modulation of transient outward current I to in the human heart suggests that pathogenic variations in the KCNE3 gene can underlie the development of BrS. 62 Gain-of-function pathogenic variants in the KCND3-encoded K v 4.3 potassium channel are implicated in the pathogenesis and phenotypic expression of BrS, inducing lethal arrhythmia that has been precipitated by a genetically enhanced I to current gradient within the right ventricle. 63 Interestingly, the KCNE5 gene is located on the X chromosome, adding a new pattern of inheritance for BrS.…”

The genetic basis of Brugada syndrome: A mutation update

“…The Kv:KCNE ion channel complexes are heterohexameric structures consisting of four a-subunits and two KCNE peptides [Morin and Kobertz, 2008]. The KCNE peptides modulate several potassium currents in the heart [Abbott and Goldstein, 2002;Abbott et al, 1999;Grunnet et al, 2003;Lewis et al, 2004;McCrossan et al, 2003;Yu et al, 2001;Zhang et al, 2001], including I Ks [Bendahhou et al, 2005], I Kr [Abbott and Goldstein, 2002], and possibly I to [Delpon et al, 2008]. The minK peptide, encoded by KCNE1, has been shown convincingly to confer a slow activation to the KCNQ1 channel, characteristic of the I Ks current, whereas the MiRP2:KCNQ1 complex is a constitutively active potassium channel [Schroeder et al, 2000].…”

“…Fig. S1), who were heterozygous carriers of a missense mutation, R99H, in KCNE3 [Delpon et al, 2008] (see Table 2 and Fig. 4).…”

Fever Induced Brugada Syndrome

“…Of these, mutations in cardiac sodium channel SCN genes (SCN5A and SCN10A) are the most well-known [11]. Since all affected families do not have these mutations, it is believed that other mutations in sodium channel genes or mutations in non-sodium channel genes may also cause Brugada syndrome [12][13][14][15].There have been some cases with a normal baseline EKG where in a Brugada pattern was induced by factors such fever, infection, cocaine use and even medication, particularly sodium channel blocking agents. With SCD being a common presenting symptom, it is critical to make an early diagnosis and institute preventive treatment such as an implantable cardioverter defi brillator.…”

“…Of these, mutations in cardiac sodium channel SCN genes (SCN5A and SCN10A) are the most well-known [11]. Since all affected families do not have these mutations, it is believed that other mutations in sodium channel genes or mutations in non-sodium channel genes may also cause Brugada syndrome [12][13][14][15].…”