ALK2 mutation in a patient with Down's syndrome and a congenital heart defect

Irene C. Joziasse, Kelly A. Smith, Sonja Chocron, Maarten Van Dinther, Victor Guryev, Jasper J. Van De Smagt, Edwin Cuppen, Peter Ten Dijke, Barbara J.M. Mulder, Cheryl L. Maslen, Benjamin Reshey, Pieter A. Doevendans, Jeroen Bakkers

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs.

Original languageEnglish (US)
Pages (from-to)389-393
Number of pages5
JournalEuropean Journal of Human Genetics
Issue number4
StatePublished - Apr 2011
Externally publishedYes


  • Down's syndrome
  • congenital heart defects
  • gene mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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