Altered TGFΒ signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type i caused by fibulin-4 deficiency

Marjolijn Renard, Tammy Holm, Regan Veith, Bert L. Callewaert, Lesley C. Adès, Osman Baspinar, Angela Pickart, Majed Dasouki, Juliane Hoyer, Anita Rauch, Pamela Trapane, Michael G. Earing, Paul J. Coucke, Lynn Y. Sakai, Harry C. Dietz, Anne M. De Paepe, Bart L. Loeys

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins prominently expressed in medial layers of large veins and arteries. Involvement of the FBLN4 gene in cardiovascular pathology was shown in a murine model and in three patients affected with cutis laxa in association with systemic involvement. To elucidate the contribution of FBLN4 in human disease, we investigated two cohorts of patients. Direct sequencing of 17 patients with cutis laxa revealed no FBLN4 mutations. In a second group of 22 patients presenting with arterial tortuosity, stenosis and aneurysms, FBLN4 mutations were identified in three patients, two homozygous missense mutations (p.Glu126Lys and p.Ala397Thr) and compound heterozygosity for missense mutation p.Glu126Val and frameshift mutation c.577delC. Immunoblotting analysis showed a decreased amount of fibulin-4 protein in the fibroblast culture media of two patients, a finding sustained by diminished fibulin-4 in the extracellular matrix of the aortic wall on immunohistochemistry. pSmad2 and CTGF immunostaining of aortic and lung tissue revealed an increase in transforming growth factor (TGF)Β signaling. This was confirmed by pSmad2 immunoblotting of fibroblast cultures. In conclusion, patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis. This confirms the important role of fibulin-4 in vascular elastic fiber assembly. Furthermore, we provide the first evidence for the involvement of altered TGFΒ signaling in the pathogenesis of FBLN4 mutations in humans.

Original languageEnglish (US)
Pages (from-to)895-901
Number of pages7
JournalEuropean Journal of Human Genetics
Issue number8
StatePublished - Aug 2010


  • TGFβ
  • aortic aneurysm
  • arterial tortuosity
  • cutis laxa
  • fibulin-4

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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