Document Detail

Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations.
MedLine Citation:
PMID:  20501893     Owner:  NLM     Status:  MEDLINE    
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetically inheritable vascular dysplasia caused by mutations in genes encoding receptors of the transforming growth factor-beta (TGF-beta) family: ENG, encoding endoglin (HHT1), and ACVRL1, encoding activin receptor-like kinase-1 (ALK1; HHT2). Our recent discovery of bone morphogenetic protein 9 (BMP9) as the specific ligand for ALK1 allowed us to reevaluate the functional significance of ACVRL1 mutations. We generated 19 ALK1 mutants reproducing HHT2 mutations (4 were novel mutations) found throughout the protein. We show that all ALK1 mutant proteins were expressed by transfected cells; most of them were present at the cell surface and retained their ability to bind BMP9 (except for the extracellular mutants). However, most were defective in BMP9 signaling. None of the ALK1 mutants had a dominant negative effect on wild-type ALK1 activity. These data demonstrate that mutations of ACVRL1 fit with a functional haploinsufficiency model affecting BMP9 signaling. Our study also identified 4 ACVRL1 mutations (D179A, R386C, R454W, and A482V) that did not alter the BMP9 responses that are polymorphisms and 2 novel mutations that are pathogenic (L381P and I485F). This demonstrates that the analysis of BMP9 responses can be used as a diagnostic tool by geneticists confronted with novel or conflicting ACVRL1 mutations.
Nicolas Ricard; Marie Bidart; Christine Mallet; Gaetan Lesca; Sophie Giraud; Renaud Prudent; Jean-Jacques Feige; Sabine Bailly
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-25
Journal Detail:
Title:  Blood     Volume:  116     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-03     Completed Date:  2010-10-07     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1604-12     Citation Subset:  AIM; IM    
Inserm, U, Grenoble, France.
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MeSH Terms
Activin Receptors, Type II / genetics*
Blotting, Western
Flow Cytometry
Growth Differentiation Factors / metabolism*
Luciferases / metabolism
Mutation / genetics*
NIH 3T3 Cells
Telangiectasia, Hereditary Hemorrhagic / diagnosis*,  genetics*
Reg. No./Substance:
0/GDF2 protein, human; 0/Growth Differentiation Factors; EC 1.13.12.-/Luciferases; EC protein, human; EC Receptors, Type II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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