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

Irene C Joziasse (1) , Kelly A Smith (1) , Sonja Chocron (1) , Maarten van Dinther (1) , Guryev Victor (1) , Jasper van Der Smagt (1) , Edwin Cuppen (1) , Peter ten Dijke (1) , Barbara Mulder (1) , Cheryl L Maslen (1) , Benjamin Reshey (1) , Pieter A Doevendans (1) , Jeroen Bakkers (1)

1 cardiology

Down syndrome, resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects. Although increased dosage of chromosome 21 sequences are likely to be part of the etiology of cardiac defects, only a proportion of Down syndrome patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large candidate gene sequencing screen in patients with atrioventricular septal defects, substitution were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with Down syndrome 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 Down syndrome background, ALK2 mediated reduction of BMP signalling may contribute to congenital heart defects.

Mots clés: Down Syndrome; Congenital Heart Defects; gene mutation

Irene C Joziasse, Kelly A Smith, Sonja Chocron, Maarten van Dinther, Guryev Victor, et al.. ALK2 mutation in a patient with Down syndrome and a congenital heart defect. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2010.224⟩. ⟨hal-00609408⟩