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Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia.

ABSTRACT: To identify mutations that cause hereditary hemorrhagic telangiectasia (HHT, or Rendu-Osler-Weber syndrome), clinical evaluations and genetic studies were performed on 32 families. Linkage studies in four of eight families indicated an endoglin (ENG) gene mutation. ENG sequences of affected members of the four linked families and probands from the 24 small families were screened for mutations, by Southern blot analyses and by cycle sequencing of PCR-amplified DNA. Seven novel mutations were identified in eight families. Two mutations (a termination codon in exon 4 and a large genomic deletion extending 3' of intron 8) did not produce a stable ENG transcript in lymphocytes. Five other mutations (two donor splice-site mutations and three deletions) produce altered mRNAs that are predicted to encode markedly truncated ENG proteins. Mutations in other families are predicted to lie in ENG-regulatory regions or in one of the additional genes that may cause HHT. These data suggest that the molecular mechanism by which ENG mutations cause HHT is haploinsufficiency. Furthermore, because the clinical manifestation of disease in these eight families was similar, we hypothesize that phenotypic variation of HHT is not related to a particular ENG mutation.

SUBMITTER: Shovlin CL

PROVIDER: S-EPMC1715873 | biostudies-other | 1997 Jul

REPOSITORIES: biostudies-other

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Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia.

Shovlin C L CL Hughes J M JM Scott J J Seidman C E CE Seidman J G JG

American journal of human genetics 19970701 1

To identify mutations that cause hereditary hemorrhagic telangiectasia (HHT, or Rendu-Osler-Weber syndrome), clinical evaluations and genetic studies were performed on 32 families. Linkage studies in four of eight families indicated an endoglin (ENG) gene mutation. ENG sequences of affected members of the four linked families and probands from the 24 small families were screened for mutations, by Southern blot analyses and by cycle sequencing of PCR-amplified DNA. Seven novel mutations were iden ...[more]

PMID: 9245986

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Project description:BackgroundHereditary hemorrhagic telangiectasia (HHT) is a vascular multi-organ system disorder. Its diagnostic criteria include epistaxis, telangiectases in mucocutaneous sites, arteriovenous malformations (AVMs), and familial inheritance. HHT is transmitted as an autosomal dominant condition, caused in 85% of cases by mutations in either Endoglin (ENG) or Activin receptor-like kinase (ACVRL1/ACVRL1/ALK1) genes. Pathogenic mutations have been described in exons, splice junctions and, in a few cases with ENG mutations, in the proximal promoter, which creates a new ATG start site. However, no mutations affecting transcription regulation have been described to date in HHT, and this type of mutation is rarely identified in the literature on rare diseases.MethodsSequencing data from a family with HHT lead to single nucleotide change, c.-58G > A. The functionality and pathogenicity of this change was analyzed by in vitro mutagenesis, quantitative PCR and Gel shift assay. Student t test was used for statistical significance.ResultsA single nucleotide change, c.-58G > A, in the proximal ENG promoter co-segregated with HHT clinical features in an HHT family. This mutation was present in the proband and in 2 other symptomatic members, whereas 2 asymptomatic relatives did not harbor the mutation. Analysis of RNA from activated monocytes from the probands and the healthy brother revealed reduced ENG mRNA expression in the HHT patient (p = 0.005). Site-directed mutagenesis of the ENG promoter resulted in a three-fold decrease in luciferase activity of the mutant c.-58A allele compared to wild type (p = 0.005). Finally, gel shift assay identified a DNA-protein specific complex.ConclusionsThe novel ENG c.-58G > A substitution in the ENG promoter co-segregates with HHT symptoms in a family and appears to affect the transcriptional regulation of the gene, resulting in reduced ENG expression. ENG c.-58G > A may therefore be a pathogenic HHT mutation leading to haploinsufficiency of Endoglin and HHT symptoms. To the best of our knowledge, this is the first report of a pathogenic mutation in HHT involving the binding site for a transcription factor in the promoter of ENG.

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Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia.

Publications

Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia.

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