MUTANT ENDOGLIN IN HEREDITARY HEMORRHAGIC TELANGIECTASIA TYPE-1 IS TRANSIENTLY EXPRESSED INTRACELLULARLY AND IS NOT A DOMINANT-NEGATIVE

Endoglin (CD105), a component of the TGF-beta 1 receptor complex, is t he target gene for the dominantly inherited vascular disorder heredita ry hemorrhagic telangiectasia type 1 (HHT1). We have identified a nove l endoglin splice site mutation, leading to an in-frame deletion of ex on 3, in a newborn from a family with HHT. Expression of normal and mu tant endoglin proteins was analyzed in umbilical vein endothelial cell s from this baby and in activated monocytes from the affected father, In both samples, only normal dimeric endoglin (160 kD) was observed at the cell surface, at 50% of control levels, Despite an intact transme mbrane region, mutant protein was only detectable by metabolic labelin g, as an intracellular homodimer of 130 kD, In monocytes from three cl inically affected HHT1 patients, with known mutations creating prematu re stop codons in exons 8 and 10, surface endoglin was also reduced by half and no mutant was detected, Overexpression into COS-1 cells of e ndoglin cDNA truncated in exons 7 and 11, revealed their intracellular expression, inability to be secreted and to form heterodimers at the cell surface, These results indicate that mutated forms of endoglin ar e transiently expressed intracellularly and not likely to act as domin ant negative proteins, as proposed previously, A reduction in the leve l of functional endoglin is thus involved in the generation of HHT1, a nd associated arteriovenous malformations.