Document Detail

ALK2 mutation in a patient with Down's syndrome and a congenital heart defect.
MedLine Citation:
PMID:  21248739     Owner:  NLM     Status:  MEDLINE    
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.
Irene C Joziasse; Kelly A Smith; Sonja Chocron; Maarten van Dinther; Victor Guryev; Jasper J van de Smagt; Edwin Cuppen; Peter Ten Dijke; Barbara Jm Mulder; Cheryl L Maslen; Benjamin Reshey; Pieter A Doevendans; Jeroen Bakkers
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-01-19
Journal Detail:
Title:  European journal of human genetics : EJHG     Volume:  19     ISSN:  1476-5438     ISO Abbreviation:  Eur. J. Hum. Genet.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-03-17     Completed Date:  2011-07-06     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  9302235     Medline TA:  Eur J Hum Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  389-93     Citation Subset:  IM    
Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
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MeSH Terms
Activin Receptors, Type I / chemistry,  genetics*,  metabolism
Bone Morphogenetic Protein 1 / metabolism
Down Syndrome / complications,  genetics*
Heart Defects, Congenital / diagnosis,  etiology*,  genetics*
Heart Septal Defects, Atrial / genetics,  pathology
Mutation / genetics*
Protein Conformation
Zebrafish / genetics
Reg. No./Substance:
EC protein, human; EC Receptors, Type I; EC Morphogenetic Protein 1

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