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

Détails

Ressource 1Télécharger: gim2016126a.pdf (2650.62 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_BC357EF48A1B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.
Périodique
Genetics in medicine
Auteur(s)
Meester J.A., Vandeweyer G., Pintelon I., Lammens M., Van Hoorick L., De Belder S., Waitzman K., Young L., Markham L.W., Vogt J., Richer J., Beauchesne L.M., Unger S., Superti-Furga A., Prsa M., Dhillon R., Reyniers E., Dietz H.C., Wuyts W., Mortier G., Verstraeten A., Van Laer L., Loeys B.L.
ISSN
1530-0366 (Electronic)
ISSN-L
1098-3600
Statut éditorial
Publié
Date de publication
04/2017
Peer-reviewed
Oui
Volume
19
Numéro
4
Pages
386-395
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.
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.
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.
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.

Mots-clé
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
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/09/2016 18:45
Dernière modification de la notice
20/08/2019 16:30
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