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Hereditary hemorrhagic telangiectasia type 1 (HHT1) is associated with mutations in the ENDOGLIN gene which normally codes for a polypeptide of 653 amino acids expressed at the cell surface as a dimeric glycoprotein. To maximize the detection of potential mutant proteins, we analyzed by pulse-chase experiments the expression of large truncation mutants in endothelial cells from newborns with HHT1. A mutant truncated at residue 490 (Delta490) and the Delta517 mutant, previously suggested to act as dominant negative, were undetectable. Proteins Delta471 and Delta571 were barely detectable as transient monomers of 62 and 72 kDa. A de novo 13 bp deletion in exon 11 encoded a monomeric protein of 70 kDa (Delta557), present at low levels in activated monocytes. Six novel missense mutants and DeltaS411 were expressed only as the 80 kDa intracellular precursor of surface endoglin, suggesting impaired processing. All nine novel mutations reported failed to be expressed other than intracellularly. Several constructs of endoglin were expressed in COS-1 cells; only the full-length protein was processed to the cell surface. Recombinant Delta586, corresponding to the complete extracellular domain, was secreted as monomeric and dimeric glycosylated species. Our studies show that all HHT1 mutants analyzed, although expressed to various degrees in COS-1 cells, are either undetectable, present at low levels as transient intracellular forms, or expressed as partially glycosylated precursors in endogenous cells. These mutants do not form heterodimers with normal endoglin and do not interfere with its normal trafficking to the cell surface, further supporting the haploinsufficiency model.

Analysis of several endoglin mutants reveals no endogenous mature or secreted protein capable of interfering with normal endoglin function