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

Michael Benzinou, Frederic F. Clermont, Tom G W Letteboer, Jai Hyun Kim, Silvia Espejel, Kelly A. Harradine, Juan Arbelaez, Minh Thu Luu, Ritu Roy, David Quigley, Mamie Nakayama Higgins, Musa Zaid, Bradley E. Aouizerat, Johannes Kristian Ploos Van Amstel, Sophie Giraud, Sophie Dupuis-Girod, Gaetan Lesca, Henri Plauchu, Christopher C W Hughes, Cornelius J J WestermannRosemary J. Akhurst

Research output: Contribution to journalArticlepeer-review


Hereditary haemorrhagic telangiectasia (HTT) is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HTT 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 HTT, 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 HTT in particular and to angiogenesis in general.

Original languageEnglish (US)
Article number616
JournalNature communications
StatePublished - 2012

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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