A single hERG mutation underlying a spectrum of acquired and congenital long QT syndrome phenotypes.
J Mol Cell Cardiol
; 43(1): 63-72, 2007 Jul.
Article
en En
| MEDLINE
| ID: mdl-17531263
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Síndrome de QT Prolongado
/
Canales de Potasio Éter-A-Go-Go
/
Enfermedades Genéticas Congénitas
Tipo de estudio:
Prognostic_studies
Límite:
Aged
/
Female
/
Humans
País/Región como asunto:
America do norte
/
Europa
Idioma:
En
Revista:
J Mol Cell Cardiol
Año:
2007
Tipo del documento:
Article
País de afiliación:
Bélgica
Pais de publicación:
Reino Unido