期刊
GENETICS IN MEDICINE
卷 19, 期 4, 页码 386-395出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2016.126
关键词
biglycan; BGN; Loeys-Dietz syndrome; Marfan syndrome; thoracic aortic aneurysm
资金
- University of Antwerp (Lancer-ingsproject)
- Fund for Scientific Research, Flanders (FWO, Belgium) [G.0221.12]
- Dutch Heart Foundation [20131093]
- Fondation Leducq (MIBAVA-Leducq) [12CVD03]
- National Marfan Foundation
- Scientific Research, Flanders
- European Research Council [ERC- StG-2012-30972-BRAVE]
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-beta 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-beta signaling.
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