title: Characterization of 17 novel endoglin mutations associated with hereditary hemorrhagic telangiectasia.
abstract: Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a vascular dysplasia caused by mutations in the endoglin (ENG) gene and associated with epistaxis, telangiectases, and a high incidence of pulmonary arteriovenous malformations. To efficiently detect deletions and insertions, we optimized a quantitative multiplex polymerase chain reaction (QMPCR) analysis. We report 17 novel mutations, of which six were detected by QMPCR. Three deletions occurring in intronic sequences were associated with a single copy of exons 9a-14, exon 5, and exons 7-8, respectively. A transient 70kDa monomeric mutant protein resulted from the in-frame deletion of exons 7 and 8 but no mutant protein was present in the other cases. Deletion (in exon 10) or insertion (in exon 7) of two nucleotides, as well as a 1-bp deletion in the small exon 9a were found by QMPCR. Sequencing was required to detect single nucleotide deletions/insertions in exons 2, 5, 6, and 8. No mutant proteins were associated with these frame shift mutations. Two novel splice site mutations resulted in skipping of exons 2 and 4, respectively, while a previously reported intron 3 splice mutant was observed as a de novo mutation. We also report five novel nonsense and missense mutations, including one de novo. Review of the 80 HHT1 families reported to date indicates that 10% would not be resolved by sequencing and that an additional 25% could be revealed by QMPCR performed prior to sequencing. Thus the use of QMPCR accelerates genetic screening for HHT1 and resolves mutations affecting whole exons.
authors.affiliation: Cancer and Blood Research Program, The Hospital for Sick Children and Department of Immunology, University of Toronto, Ontario, Canada.
authors.forename: Urszula
authors.initials: U
authors.lastname: Cymerman
authors.forename: Sonia
authors.initials: S
authors.lastname: Vera
authors.forename: Amna
authors.initials: A
authors.lastname: Karabegovic
authors.forename: Salma
authors.initials: S
authors.lastname: Abdalla
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D000071063:Endoglin; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011956:Receptors, Cell Surface; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics* / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D018076:DNA, Complementary; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; D004247:DNA