Abstract
Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by facial dysmorphism, cleft palate, dilation of the aortic arch, blood vessel tortuosity and a high risk of aortic dissection. It is caused by mutations in the transforming growth factor β-receptor 1 and 2 (TGFβ-R1 and TGFβ-R2) genes. Fibroblasts derived from 12 Loeys–Dietz syndrome patients, six with TGFB-R1 mutations and six with TGFB-R2 mutations, were analyzed using RT-PCR, biochemical assays, immunohistochemistry and electron microscopy for production of elastin, fibrillin 1, fibulin 1 and fibulin 4 and deposition of collagen type I. All LDS fibroblasts with TGFβ-R1 mutations demonstrated decreased expression of elastin and fibulin 1 genes and impaired deposition of elastic fibers. In contrast, fibroblasts with TGFβ-R2 mutations consistently demonstrated intracellular accumulation of collagen type I in the presence of otherwise normal elastic fiber production. Treatment of the cell cultures with dexamethasone induced remarkable upregulation in the expression of tropoelastin, fibulin 1- and fibulin 4-encoding mRNAs, leading to normalization of elastic fiber production in fibroblasts with TGFβ-R1 mutations. Treatment with dexamethasone also corrected the abnormal secretion of collagen type I from fibroblasts with TGFβ-R2 gene mutations. As the organogenesis-relevant elastic fiber production occurs exclusively in late fetal and early neonatal life, these findings may have implications for treatment in early life. Further studies are required to determine if dexamethasone treatment of fetuses prenatally diagnosed with LDS would prevent or alleviate the connective tissue and vascular defects seen in this syndrome.
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Acknowledgements
This work was supported by the Canadian Institute of Health Research through grant PG 13920 and by the Heart and Stroke Foundation of Ontario through grant NA 5435 to AH. We are grateful to Dr H Dietz from Johns Hopkins Medical Center, USA, for sharing fibroblasts derived from his LDS patients.
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Barnett, C., Chitayat, D., Bradley, T. et al. Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys–Dietz syndrome fibroblasts: a possible treatment?. Eur J Hum Genet 19, 624–633 (2011). https://doi.org/10.1038/ejhg.2010.259
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DOI: https://doi.org/10.1038/ejhg.2010.259
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