Human Molecular Genetics, Vol 8, 2171-2181, Copyright © 1999 by Oxford University Press
N Pece-Barbara, U Cymerman, S Vera, DA Marchuk and M Letarte
ENDOGLIN codes for a homodimeric membrane glycoprotein that interacts with
receptors for members of the TGF-beta superfamily and is the gene mutated
in the autosomal dominant vascular disorder hereditary hemorrhagic
telangiectasia type 1 (HHT1). We recently demonstrated that functional
endoglin was expressed at half levels on human umbilical vein endothelial
cells (HUVECs) and peripheral blood activated monocytes from HHT1 patients.
Two types of mutant protein were previously analyzed, the product of an
exon 3 skip which was expressed as a transient intracellular species and
prematurely truncated proteins that were undetectable in patient samples.
Here we report the analysis of four proteins resulting from point
mutations, with missense codons G52V and C53R in exon 2, W149C in exon 4
and L221P in exon 5. Metabolic labeling of activated monocytes from
confirmed, clinically affected patients revealed reduced expression of
fully processed normal endoglin in all cases. Pulse-chase analysis with
HUVECs from a newborn with the C53R substitution indicated that mutant
endoglin remained intracellular as a precursor form and did not impair
processing of the normal protein. Biotinylation of cell surface proteins,
metabolic labeling and pulse-chase analysis revealed that none of the
engineered missense mutants was significantly expressed at the surface of
COS-1 transfectants. Thus, these four HHT1 missense mutations lead to
transient intracellular species which cannot interfere with normal endoglin
function. These data suggest that haploinsufficiency, leading to reduced
levels of one of the major surface glyco-proteins of vascular endothelium,
is the predominant mechanism underlying the HHT1 phenotype.
ARTICLES
Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1
Cancer and Blood Research Programme, Hospital for Sick Children and Department of Immunology, University of Toronto, 555 University Avenue, Toronto M5G 1X8, Canada and
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