Dominant-negative alk2 allele associates with congenital heart defects

Smith, Kelly A., Joziasse, Irene C., Chocron, Sonja, Van Dinther, Maarten, Guryev, Victor, Verhoeven, Manon C., Rehmann, Holger, Van Der Smagt, Jasper J., Doevendans, Pieter A., Cuppen, Edwin, Mulder, Barbara J., Ten Dijke, Peter and Bakkers, Joeroen (2009) Dominant-negative alk2 allele associates with congenital heart defects. Circulation, 119 24: 3062-3069. doi:10.1161/CIRCULATIONAHA.108.843714

Author Smith, Kelly A.
Joziasse, Irene C.
Chocron, Sonja
Van Dinther, Maarten
Guryev, Victor
Verhoeven, Manon C.
Rehmann, Holger
Van Der Smagt, Jasper J.
Doevendans, Pieter A.
Cuppen, Edwin
Mulder, Barbara J.
Ten Dijke, Peter
Bakkers, Joeroen
Title Dominant-negative alk2 allele associates with congenital heart defects
Journal name Circulation   Check publisher's open access policy
ISSN 0009-7322
Publication date 2009-06-23
Year available 2009
Sub-type Article (original research)
DOI 10.1161/CIRCULATIONAHA.108.843714
Open Access Status
Volume 119
Issue 24
Start page 3062
End page 3069
Total pages 8
Place of publication Baltimore, MD United States
Publisher Lippincott Williams & Wilkins
Collection year 2009
Language eng
Subject 2737 Physiology (medical)
2705 Cardiology and Cardiovascular Medicine
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 AND RESULTS: 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 proteinspecific 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. CONCLUSION: These data identify the dominant-negative allele ALK2 L343P in a patient with AVS defects.
Keyword ALK2 protein, human
Heart defects, congenital
Signal transduction
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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