|
Title
|
|
|
|
Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections
| |
|
Author
|
|
|
|
| |
|
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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Genetics in medicine. - Philadelphia, Pa.
| |
|
Publication
|
|
|
|
Philadelphia, Pa.
:
2017
| |
|
ISSN
|
|
|
|
1098-3600
1530-0366
| |
|
DOI
|
|
|
|
10.1038/GIM.2016.126
| |
|
Volume/pages
|
|
|
|
19
:4
(2017)
, p. 386-395
| |
|
ISI
|
|
|
|
000399067600003
| |
|
Pubmed ID
|
|
|
|
27632686
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|