ALK2 mutation in a patient with Down's syndrome and a congenital heart defect.
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.
Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Irene C
IC
Joziasse
Kelly A
KA
Smith
Sonja
S
Chocron
Maarten
M
van Dinther
Victor
V
Guryev
Jasper J
JJ
van de Smagt
Edwin
E
Cuppen
Peter
P
Ten Dijke
Barbara Jm
BJ
Mulder
Cheryl L
CL
Maslen
Benjamin
B
Reshey
Pieter A
PA
Doevendans
Jeroen
J
Bakkers
D030201:Activin Receptors, Type I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D055395:Bone Morphogenetic Protein 1 / Q000378:metabolism; D002417:Cattle; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D005260:Female; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics*; D006344:Heart Septal Defects, Atrial / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D015027:Zebrafish / Q000235:genetics
C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D055395:Bone Morphogenetic Protein 1
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