Absence of cardiovascular manifestations in a haploinsufficient Tgfbr1 mouse model

PLoS One. 2014 Feb 24;9(2):e89749. doi: 10.1371/journal.pone.0089749. eCollection 2014.


Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor β (TGFβ)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGFβ receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGFβ signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378* nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno)histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiovascular Abnormalities / genetics*
  • Codon, Nonsense / genetics
  • Disease Models, Animal*
  • Echocardiography
  • Fluorescence
  • Genotype
  • Haploinsufficiency / physiology*
  • Immunohistochemistry
  • Loeys-Dietz Syndrome / genetics*
  • Loeys-Dietz Syndrome / physiopathology*
  • Mice
  • Positron-Emission Tomography
  • Protein Serine-Threonine Kinases / deficiency*
  • Protein Serine-Threonine Kinases / genetics
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / deficiency*
  • Receptors, Transforming Growth Factor beta / genetics
  • Statistics, Nonparametric
  • X-Ray Microtomography


  • Codon, Nonsense
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse

Grant support

This study was partly supported by the Fund for Scientific Research, Flanders (Belgium) [G.0094.06]; Fighting Aneurysmal Disease [EC-FP7]; the Special Research Fund of the Ghent University [BOF10/GOA/005]; and a Methusalem grant from the Flemish government and the Ghent University to A. De Paepe [08/01M01108]. B. Loeys, J. De Backer, B. Callewaert, and M. Renard are/were, respectively, senior clinical investigators (BL and JDB), postdoctoral fellow (BC), and PhD fellow (MR) supported by the Fund for Scientific Research, Flanders (Belgium). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.