Abstract
BackgroundsThe Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor β (TGF-β) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. In order to gain further insight into the pathophysiology of the disorder, we investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS patients from a cohort of 23 patients including 6 patients with novel TGF-β receptor mutations.Methods and ResultsWe performed gene expression profiling of OECs using microarray analysis followed by quantitative PCR for verification of gene expression. Compared to OECs of age- and sex-matched healthy controls, OECs isolated from three LDS patients displayed altered expression of several genes belonging to the TGF-β pathway, especially those affecting bone morphogenic protein (BMP) signalling including BMP2, BMP4 and BMPR1A. Gene expression of BMP antagonist Gremlin-1 (GREM1) showed the most prominent up-regulation. This increase was confirmed at the protein level by immunoblotting of LDS-OECs. In immunohistochemistry, abundant Gremlin-1 protein expression could be verified in endothelial cells as well as smooth muscle cells within the arterial media. Furthermore, Gremlin-1 plasma levels of LDS patients were significantly elevated compared to healthy control subjects.ConclusionsThese findings open new avenues in the understanding of the pathogenesis of Loeys-Dietz syndrome and the development of new diagnostic serological methods for early disease detection.
Highlights
The Loeys-Dietz syndrome (LDS) is an inherited autosomal dominant connective tissue disorder described first in 2005 by Bart Loeys and Harry Dietz [1]
The Loeys-Dietz syndrome is caused by a mutation in the transforming growth factor b (TGF-b) type II receptor TGFBR2 or type I receptor TGFBR1
The great majority of mutations in Loeys-Dietz syndrome are missense mutations located within the kinase domain of TGFBR2 or TGFBR1, only three of our six novel mutations fit within this category: p.N384K and p.A414T in TGFBR2 and p.S241P in TGFBR1 which were all predicted to be probably disease causing in bioinformatic analysis
Summary
The Loeys-Dietz syndrome (LDS) is an inherited autosomal dominant connective tissue disorder described first in 2005 by Bart Loeys and Harry Dietz [1]. The Loeys-Dietz syndrome is caused by a mutation in the transforming growth factor b (TGF-b) type II receptor TGFBR2 or type I receptor TGFBR1. More than 50 different mutations in TGFBR2 or TGFBR1 have been described in LDS patients. The great majority of those mutations represent missense mutations which are located within the kinase domain of the receptor probably resulting in impaired receptor signalling [1,2,3]. Mutations in the gene for TGFB2 and the TGF-b pathway downstream mediator SMAD3 have been associated with the pathogenesis of Loeys-Dietz syndrome [4,5,6]
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