A single hERG mutation underlying a spectrum of acquired and congenital long QT syndrome phenotypes.
The long QT syndrome (LQTS) is a multi-factorial disorder that predisposes to life-threatening arrhythmias. Both hereditary and acquired subforms have been identified. Here, we present clinical and biophysical evidence that the hERG mutation c.1039 C>T (p.Pro347Ser or P347S) is responsible for both the acquired and the congenital phenotype. In one case the genotype remained silent for years until the administration of several QT-prolonging drugs resulted into a full-blown phenotype, that was reversible upon cessation of these compounds. On the other hand the mutation was responsible for a symptomatic congenital LQTS in a Dutch family, displaying a substantial heterogeneity of the clinical symptoms. Biophysical characterization of the p.Pro347Ser potassium channels using whole-cell patch clamp experiments revealed a novel pathogenic mechanism of reciprocal changes in the inactivation kinetics combined with a dominant-negative reduction of the functional expression in the heterozygous situation, yielding a modest genetic predisposition for LQTS. Our data show that in the context of the multi-factorial aetiology underlying LQTS a modest reduction of the repolarizing power can give rise to a spectrum of phenotypes originating from one mutation. This observation increases the complexity of genotype-phenotype correlations in more lenient manifestations of the disease and underscores the difficulty of predicting the expressivity of the LQTS especially for mutations with a more subtle impact such as p.Pro347Ser.
Saenen
J B
JB
Laboratory for Molecular Biophysics, Physiology and Pharmacology, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
Paulussen
A D C
AD
Jongbloed
R J
RJ
Marcelis
C L
CL
Gilissen
R A H J
RA
Aerssens
J
J
Snyders
D J
DJ
Raes
A L
AL
D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D002170:Canada; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D030342:Genetic Diseases, Inborn; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D009426:Netherlands; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D044465:White People
D051638:Ether-A-Go-Go Potassium Channels