BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia

Am J Hum Genet. 2013 Sep 5;93(3):530-7. doi: 10.1016/j.ajhg.2013.07.004. Epub 2013 Aug 22.

Abstract

Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-β) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Substitution / genetics
  • Animals
  • Blood Vessels / abnormalities*
  • Female
  • Genetic Predisposition to Disease
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors / genetics*
  • Humans
  • Ligands
  • Male
  • Mice
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Phenotype
  • Protein Binding
  • Protein Processing, Post-Translational
  • Signal Transduction / genetics
  • Syndrome
  • Telangiectasia, Hereditary Hemorrhagic / genetics*
  • Telangiectasia, Hereditary Hemorrhagic / pathology*
  • Transforming Growth Factor beta / genetics
  • Zebrafish / genetics

Substances

  • GDF2 protein, human
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors
  • Ligands
  • Transforming Growth Factor beta