Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections

Genet Med. 2017 Apr;19(4):386-395. doi: 10.1038/gim.2016.126. Epub 2016 Sep 15.

Abstract

Purpose: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families.

Methods: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed.

Results: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture.

Conclusion: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneurysm, Dissecting / genetics*
  • Aneurysm, Dissecting / metabolism
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Aneurysm, Thoracic / metabolism
  • Biglycan / genetics*
  • Biglycan / metabolism
  • Cells, Cultured
  • Female
  • Genes, X-Linked
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mutation*
  • Pedigree
  • Sequence Analysis, DNA / methods
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism

Substances

  • BGN protein, human
  • Biglycan
  • Transforming Growth Factor beta