Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections
Publication year
2017Author(s)
Source
Genetics in Medicine, 19, 4, (2017), pp. 386-395ISSN
Publication type
Article / Letter to editor

Display more detailsDisplay less details
Organization
Human Genetics
Journal title
Genetics in Medicine
Volume
vol. 19
Issue
iss. 4
Page start
p. 386
Page end
p. 395
Subject
Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health SciencesAbstract
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.Genet Med 19 4, 386-395.
This item appears in the following Collection(s)
- Academic publications [227881]
- Electronic publications [107344]
- Faculty of Medical Sciences [86219]
- Open Access publications [76470]
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.