PUBLICATION

Dominant-Negative ALK2 Allele Associates With Congenital Heart Defects

Authors
Smith, K.A., Joziasse, I.C., Chocron, S., van Dinther, M., Guryev, V., Verhoeven, M.C., Rehmann, H., van der Smagt, J.J., Doevendans, P.A., Cuppen, E., Mulder, B.J., Ten Dijke, P., and Bakkers, J.
ID
ZDB-PUB-090616-45
Date
2009
Source
Circulation   119(24): 3062-3069 (Journal)
Registered Authors
Bakkers, Jeroen, Chocron, Sonja, Cuppen, Edwin, Guryev, Victor, Smith, Kelly
Keywords
ALK2 protein, human, genes, heart defects, congenital, screening, signal transduction
MeSH Terms
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Cattle
  • Alleles*
  • Heart Septal Defects/genetics
  • Heart Septal Defects/metabolism*
  • Heart Septal Defects/physiopathology
  • Myocardium/metabolism
  • Humans
  • Netherlands
  • Activin Receptors, Type I/genetics
  • Activin Receptors, Type I/metabolism*
  • Chlorocebus aethiops
  • COS Cells
  • Mutation, Missense
  • Heart/embryology
  • Heart/physiopathology
  • Female
  • Animals
  • Amino Acid Substitution
  • Male
  • Genes, Dominant*
  • Polymorphism, Single Nucleotide*
(all 23)
PubMed
19506109 Full text @ Circulation
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 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. Conclusion-These data identify the dominant-negative allele ALK2 L343P in a patient with AVS defects.
Genes / Markers
Figures
No images available
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WTchemical treatment: proteinPrim-5
WTchemical treatment: proteinPrim-5
WTchemical treatment: proteinPrim-5
furinahu119/hu119standard conditionsPrim-5
furinahu119/hu119standard conditionsPrim-5
1 - 5 of 5
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu119
    		Point Mutation
    s849TgTransgenic Insertion
      1 - 2 of 2
      Show
      Human Disease / Model
      Human Disease Fish Conditions Evidence
      congenital heart diseaseTAS
      1 - 1 of 1
      Show
      Sequence Targeting Reagents
      No data available
      Fish
      Fish
      furinahu119/hu119
      s849Tg
      WT
      1 - 3 of 3
      Show
      Antibodies
      Orthology
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
      Show
      Mapping
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      Citation
      Smith, K.A., Joziasse, I.C., Chocron, S., van Dinther, M., Guryev, V., Verhoeven, M.C., Rehmann, H., van der Smagt, J.J., Doevendans, P.A., Cuppen, E., Mulder, B.J., Ten Dijke, P., and Bakkers, J. (2009) Dominant-Negative ALK2 Allele Associates With Congenital Heart Defects. Circulation. 119(24):3062-3069.