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

Hum Mutat. 2006 Jun;27(6):598. doi: 10.1002/humu.9421.


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 mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / genetics*
  • Age Factors
  • Antigens, CD / genetics*
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • DNA Mutational Analysis
  • Endoglin
  • France / epidemiology
  • Genetic Linkage
  • Genetic Testing
  • Germ-Line Mutation
  • Humans
  • Mutation*
  • Polymorphism, Genetic
  • Receptors, Cell Surface / genetics*
  • Smad Proteins / genetics
  • Telangiectasia, Hereditary Hemorrhagic / diagnosis
  • Telangiectasia, Hereditary Hemorrhagic / epidemiology
  • Telangiectasia, Hereditary Hemorrhagic / genetics*


  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • Receptors, Cell Surface
  • Smad Proteins
  • ACVRL1 protein, human
  • Activin Receptors, Type II
  • BMPR1A protein, human
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II