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

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 only explain 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 carried out. 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 stainings revealed an increase in TGF-β signalling, evidenced by an increase in nuclear pSMAD2 in aortic wall. Our results are in line with 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, associated with preservation of elastic fibres and increased TGF-β signalling.

Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome

“…The study of monogenic syndromic presentations of thoracic aortic aneurysm has implicated perturbation of TGF-β signaling in disease pathogenesis (2). Primary mutations have been identified in genes encoding factors along the entire TGF-β signaling cascade, including extracellular regulators of TGF-β bioavailability (fibrillin-1 or biglycan), TGF-β ligands (TGF-β2 or TGF-β3), receptor subunits (TβRI or TβRII), as well as positive (SMAD2, SMAD3) and negative (SKI) signaling effectors (12)(13)(14)(15)(16)(17)(18)(47)(48)(49)(50)(51). Ambiguity about the precise role of TGF-β in vessel wall homeostasis has arisen because of apparently contradictory observations and ing-competent CNC counterparts in the aortic media.…”

Diabetes and aortic aneurysm: current state of the art

“… 41 Moreover, biglycan gene defects cause an X-linked syndromic form of severe TAA and dissection. 42 To better understand the role of biglycan in aneurysmal pathology, experimental models were used. Biglycan deficiency in Ldlr −/− mice aggravated angiotensin II-induced aortic aneurysm, with increased rates of vascular mortality and rupture, and induced the development of descending TAA.…”

Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome

“…Both hypertelorism and cleft palate/bifid uvula are characteristic of LDS and not frequently observed in other syndromic aortic aneurysm forms, including MFS. However, recently a new severe syndromic form of thoracic aortic aneurysm was described, caused by mutations in the gene BGN, in which uvula anomalies and hypertelorism have also been described (40). In a subset of LDS patients (mostly TGFBR1/2 mutation carries), craniosynostosis is frequently observed, especially in more severely affected patients.…”