Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia

Nat Commun. 2012 Jan 10;3:616. doi: 10.1038/ncomms1633.


Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-β pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1(-/-) mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, [corrected] as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HHT [corrected] in particular and to angiogenesis in general.

Publication types

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

MeSH terms

  • Activin Receptors, Type I / metabolism
  • Activin Receptors, Type II / metabolism
  • Animals
  • Chromosome Mapping
  • Ephrin-B2 / metabolism
  • Exons
  • Female
  • Genetic Variation
  • Haplotypes
  • Humans
  • Male
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Genetic
  • Mutation
  • Phenotype
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / physiology*
  • Species Specificity
  • Telangiectasia, Hereditary Hemorrhagic / genetics*
  • Transforming Growth Factor beta / metabolism


  • Ephrin-B2
  • Transforming Growth Factor beta
  • ACVRL1 protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse
  • PTPN14 protein, human
  • PTPN14 protein, mouse
  • Protein Tyrosine Phosphatases, Non-Receptor