R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation.
BACKGROUND
Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K(+) channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF). However, KCNQ1 mutation pleiotropy, which is capable of expressing both LQT1 and FAF, has not been demonstrated for a discrete KCNQ1 mutation. The genotype-phenotype relationship for a family with FAF suggests a possible association with the LQT1 p.Arg231Cys-KCNQ1 (R231C-Q1) mutation.


OBJECTIVE
The purpose of this study was to determine whether R231C-Q1 also can be linked to FAF.


METHODS
The R231C-Q1 proband with AF underwent genetic testing for possible mutations in 10 other AF-linked genes plus KCNH2 and SCN5A. Sixteen members from five other R231C-positive LQT1 families were genetically tested for 21 single nucleotide polymorphisms (SNPs) to determine if the FAF family had discriminatory SNPs associated with AF. R231C-Q1 was expressed with KCNE1 (E1) in HEK293 cells, and Q1E1 currents (I(Q1E1)) were analyzed using the whole-cell patch-clamp technique.


RESULTS
Genetic analyses revealed no additional mutations or discriminatory SNPs. Cells expressing WT-Q1 and R231C-Q1 exhibited some constitutively active I(Q1E1) and smaller maximal I(Q1E1) compared to cells expressing WT-Q1.


CONCLUSIONS
Constitutively active I(Q1E1) and a smaller peak I(Q1E1) are common features of FAF-associated and LQT1-associated mutations, respectively. These data suggest that the mixed functional properties of R231C-Q1 may predispose some families to LQT1 or FAF. We conclude that R231C is a pleiotropic missense mutation capable of LQT1 expression, AF expression, or both.
Bartos
Daniel C
DC
University of Kentucky, Lexington, Kentucky, USA.
Duchatelet
Sabine
S
Burgess
Don E
DE
Klug
Didier
D
Denjoy
Isabelle
I
Peat
Rachel
R
Lupoglazoff
Jean-Marc
JM
Fressart
Véronique
V
Berthet
Myriam
M
Ackerman
Michael J
MJ
January
Craig T
CT
Guicheney
Pascale
P
Delisle
Brian P
BP
D000328:Adult; D001281:Atrial Fibrillation / Q000235:genetics; D019295:Computational Biology; D005260:Female; D058685:Genetic Pleiotropy / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D029597:Romano-Ward Syndrome / Q000235:genetics*
D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human