CHARACTERIZATION OF ENDOGLIN AND IDENTIFICATION OF NOVEL MUTATIONS INHEREDITARY HEMORRHAGIC TELANGIECTASIA

To identify mutations that cause hereditary hemorrhagic telangiectasia (HHT, or Rendu-Osler-Weber syndrome), clinical evaluations and geneti c studies were performed on 32 families. Linkage studies in four of ei ght families indicated an endoglin (ENG) gene mutation. ENG sequences of affected members of the four linked families and probands from the 24 small families were screened for mutations, by Southern blot analys es and by cycle sequencing of PCR-amplified DNA. Seven novel mutations were identified in eight families. Two mutations (a termination codon in exon 4 and a large genomic deletion extending 3' of intron 8) did not produce a stable ENG transcript in lymphocytes. Five other mutatio ns (two donor splice-site mutations and three deletions) produce alter ed mRNAs that are predicted to encode markedly truncated ENG proteins. Mutations in other families are predicted to lie in ENG-regulatory re gions or in one of the additional genes that may cause HHT. These data suggest that the molecular mechanism by which ENG mutations cause HHT is haploinsufficiency. Furthermore, because the clinical manifestatio n of disease in these eight families was similar, we hypothesize that phenotypic variation of HHT is not related to a particular ENG mutatio n.