Journal Article

Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France

Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou], Rétrovirus et Pathologie Comparée (RPC) ; Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE) ; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Carette, Marie-France, Goizet, Cyril, Calender, Alain, Leheup, Bruno, Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux), Odent, Sylvie, Plauchu, Henri, Rivière, Sophie, Coulet, Florence, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pinson, Stéphane, Lesca, Gaetan, CHU Caen Normandie – Centre Hospitalier Universitaire de Caen Normandie (CHU Caen Normandie) ; Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Lefebvre, Sylvain, Cordier, Jean-François, Giraud,

2004

Overview

Hereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an autosomal dominant disease characterized by arteriovenous malformations, affecting 1 out of 10,000 individuals in France. The disease is caused by mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of ENG and ALK1 in 160 unrelated French index cases. A germline mutation was identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG, including three nonsense mutations, 19 small insertions/deletions leading to a frameshift, two inframe deletions, seven missense mutations, and five intronic or splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of 64 mutations were found in ALK1, including six nonsense mutations, 28 small insertions/deletions leading to a frameshift, one inframe deletion, 27 missense mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27 were novel mutations. Mutations were found in most parts of the coding sequence for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5, c.1103+3-1103+8del activated a cryptic splice site 22 bp upstream, and c. 1428G>A produced two abnormal transcripts, one including intron 11 and the other excluding exon 10. Although most of the mutations were private, some recurrent mutations in ALK1 were of particular interest. Mutation c.1112-1113dupG (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common haplotype, strongly suggesting a founder effect related to the concentration of patients previously reported in a specific French region (Rhone-Alpes). Three missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot.

• Publisher: Wiley,CCSD,Wiley Subscription Services, Inc., A Wiley Company,John Wiley & Sons, Inc
• Subject: Activin Receptors, Type I - genetics / Activin Receptors, Type II / ACVRL1 / ALK1 / Antigens, CD / DNA Mutational Analysis / Endoglin / ENG / founder effect / France / hemorrhagic hereditary telangiectasia / HHT1 / HHT2 / Humans / Life Sciences / Mutation / mutation screening / Osler-Rendu-Weber syndrome / Receptors, Cell Surface / Telangiectasia, Hereditary Hemorrhagic - genetics / Vascular Cell Adhesion Molecule-1 - genetics
• ISBN: 0002204717000