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.
CONCLUSION: 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.