Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.
Hum. Mutat.. 2004-03-02; 23(4): 289-299
DOI: 10.1002/humu.20017
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1. Hum Mutat. 2004 Apr;23(4):289-99.
Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic
telangiectasia in France.
Lesca G(1), Plauchu H, Coulet F, Lefebvre S, Plessis G, Odent S, Rivière S,
Leheup B, Goizet C, Carette MF, Cordier JF, Pinson S, Soubrier F, Calender A,
Giraud S; French Rendu-Osler Network.
Author information:
(1)Laboratoire de Génétique, Hôpital Edouard Herriot, Lyon, France.
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 (Rhône-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.
Copyright 2004 Wiley-Liss, Inc.
DOI: 10.1002/humu.20017
PMID: 15024723 [Indexed for MEDLINE]