Human Molecular Genetics, 2000, Vol. 9, No. 8 1227-1237
© 2000 Oxford University Press
Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2
Cancer and Blood Research Programme, The Hospital for Sick Children, and Department of Immunology, University of Toronto, Toronto M5G 1X8, Canada and 1Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain
ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming growth factor (TGF)-ß superfamily, is the gene mutated in hereditary hemorrhagic telangiectasia type 2 (HHT2) while endoglin is mutated in HHT1. Using a novel polyclonal antibody to ALK-1, we measured ALK-1 expression on human umbilical vein endothelial cells (HUVEC) of newborns from HHT families whose affected members had normal endoglin levels. ALK-1 levels were specifically reduced in three HUVEC with ALK-1 missense mutant codons, and normal in two newborns not carrying the missense mutations present in the clinically affected relatives. Levels were also normal in a HUVEC with deletion of S232 in the ATP binding site of ALK-1. Thus HHT2 appears to be associated with a loss of function of the mutant allele due to a reduction in either protein level or activity. We also report three new ALK-1 missense mutations leading to G48E/A49P, C344Y and E407D substitutions. In COS-1 transfected cells, ALK-1 was found in the TGF-ß1 and -ß3 receptor complexes in association with endoglin and TßRII, but not in activin receptor complexes containing endoglin. In HUVEC, ALK-1 was not detectable in the TGF-ß1 or -ß3 receptor complexes. However, in the absence of ligand, ALK-1 and endoglin interactions were observed by immunoprecipitation/western blot in HUVEC from normal as well as HHT1 and HHT2 patients. Our data suggest a transient association between these two proteins of the TGF-ß superfamily, both required at a critical level to ensure vessel wall integrity.
+ To whom correspondence should be addressed. Tel: +1 416 813 6258; Fax: +1 416 813 6255; Email: mablab@sickkids.on.ca
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