Human venous valve disease caused by mutations in FOXC2 and GJC2

J Exp Med. 2017 Aug 7;214(8):2437-2452. doi: 10.1084/jem.20160875.


Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation ("organization") of Prox1hi endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc1 and the gap junction proteins Gjc2, Gja1, and Gja4 were temporospatially regulated during this process. Foxc2 and Nfatc1 were coexpressed at P0, and combined Foxc2 deletion with calcineurin-Nfat inhibition disrupted early Prox1hi endothelial organization, suggesting cooperative Foxc2-Nfatc1 patterning of these events. Genetic deletion of Gjc2, Gja4, or Gja1 also disrupted early VV Prox1hi endothelial organization at postnatal day 0, and this likely underlies the VV defects seen in patients with GJC2 mutations. Knockout of Gja4 or Gjc2 resulted in reduced proliferation of Prox1hi valve-forming cells. At later stages of blood flow, Foxc2 and calcineurin-Nfat signaling are each required for growth of the valve leaflets, whereas Foxc2 is not required for VV maintenance.

MeSH terms

  • Animals
  • Cell Proliferation / genetics
  • Connexins / genetics*
  • Endothelial Cells / metabolism
  • Forkhead Transcription Factors / genetics*
  • Gap Junctions / genetics
  • Heart Valve Diseases / etiology*
  • Heart Valve Diseases / genetics*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mutation / genetics*
  • Regional Blood Flow / genetics
  • Signal Transduction / genetics
  • Venous Valves / metabolism*


  • Connexins
  • Forkhead Transcription Factors
  • connexin 47
  • mesenchyme fork head 1 protein