Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients.

Gaëtan Lesca, Nelly Burnichon, Grégory Raux, Mario Tosi, Stéphane Pinson, Marie-Jeanne Marion, Emmanuel Babin, Brigitte Gilbert-Dussardier, Sophie Rivière, Cyril Goizet, Laurence Faivre, Henri Plauchu, Thierry Frébourg, Alain Calender, Sophie Giraud,
Hum. Mutat.. 2006-01-01; 27(6): 598-598
DOI: 10.1002/humu.9421

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1. Hum Mutat. 2006 Jun;27(6):598.

Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients.

Lesca G(1), Burnichon N, Raux G, Tosi M, Pinson S, Marion MJ, Babin E,
Gilbert-Dussardier B, Rivière S, Goizet C, Faivre L, Plauchu H, Frébourg T,
Calender A, Giraud S; French Rendu-Osler Network.

Author information:
(1)Service de Génétique Moléculaire et Médicale, Hôpital Edouard Herriot, Lyon,

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease
characterized by arteriovenous malformations and resulting from mutations in two
major genes: ENG and ACVRL1. The aim of the present study was to estimate the
prevalence of the mutations of ENG and ACVRL1 in HHT, based on the largest series
of patients reported so far, recruited through a national network. We previously
reported the first mutation screening of both genes, in French HHT patients,
using heteroduplex analysis. This previous study, bringing 60 novel mutations,
provided a significant improvement to the knowledge of molecular pathology in
HHT. However, 32% (n=48) of the patients with a confirmed clinical diagnosis
remained without mutation. In these patients, we performed an extensive molecular
analysis that included the sequencing of the whole coding sequence, the search
for large rearrangements, and screening of the potential 5′ regulatory regions.
Additionally, due to the lack of large pedigrees suitable for linkage analysis,
and since SMAD4 germline mutations have been reported in families with combined
HHT and juvenile polyposis, we screened this gene and five other genes involved
in the TGF-beta/BMP pathway in the patients without mutation of ENG or ACVRL1.
Only a novel SMAD1 non-conservative substitution was found in one patient,
changing a poorly conserved methionine to an isoleucin. Twenty-three mutations
were found in ACVRL1 and 8 in ENG (including a duplication of exons 4 to 8 and
deletions of exons 1 to 3 and 9 to 14). Our results, combined with our previous
data, increase the mutation rate to 88% (n=119/136) in French patients with a
confirmed clinical diagnosis. Our results also emphasize the higher prevalence of
large insertions/deletions in ENG and the predominance of ACVRL1 over ENG

DOI: 10.1002/humu.9421
PMID: 16705692 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus