Dominant-negative ALK2 allele associates with congenital heart defects.
Circulation
; 119(24): 3062-9, 2009 Jun 23.
Article
de En
| MEDLINE
| ID: mdl-19506109
ABSTRACT
BACKGROUND:
Serious congenital heart defects occur as a result of improper atrioventricular septum (AVS) development during embryogenesis. Despite extensive knowledge of the genetic control of AVS development, few genetic lesions have been identified that are responsible for AVS-associated congenital heart defects. METHODS ANDRESULTS:
We sequenced 32 genes known to be important in AVS development in patients with AVS defects and identified 11 novel coding single-nucleotide polymorphisms that are predicted to impair protein function. We focused on variants identified in the bone morphogenetic protein receptor, ALK2, and subjected 2 identified variants to functional analysis. The coding single-nucleotide polymorphisms R307L and L343P are heterozygous missense substitutions and were each identified in single individuals. The L343P allele had impaired functional activity as measured by in vitro kinase and bone morphogenetic protein-specific transcriptional response assays and dominant-interfering activity in vivo. In vivo analysis of zebrafish embryos injected with ALK2 L343P RNA revealed improper atrioventricular canal formation.CONCLUSIONS:
These data identify the dominant-negative allele ALK2 L343P in a patient with AVS defects.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Polymorphisme de nucléotide simple
/
Récepteur activine, type 1
/
Allèles
/
Gènes dominants
/
Malformations des cloisons cardiaques
Type d'étude:
Risk_factors_studies
Limites:
Animals
/
Female
/
Humans
/
Male
Pays/Région comme sujet:
Europa
Langue:
En
Journal:
Circulation
Année:
2009
Type de document:
Article
Pays d'affiliation:
Pays-Bas