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Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment?

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 ?-receptor 1 and 2 (TGF?-R1 and TGF?-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 TGF?-R1 mutations demonstrated decreased expression of elastin and fibulin 1 genes and impaired deposition of elastic fibers. In contrast, fibroblasts with TGF?-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 TGF?-R1 mutations. Treatment with dexamethasone also corrected the abnormal secretion of collagen type I from fibroblasts with TGF?-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.

SUBMITTER: Barnett CP

PROVIDER: S-EPMC3110047 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment?

Barnett Christopher P CP Chitayat David D Bradley Timothy J TJ Wang Yanting Y Hinek Aleksander A

European journal of human genetics : EJHG 20110126 6

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, immun ...[more]

PMID: 21267002

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Project description:BACKGROUND AND PURPOSE:Loeys-Dietz syndrome (LDS) is a recently described entity that has the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Its neuroradiologic manifestations have not been well delineated. We sought to describe the neuroradiologic features of LDS and to assess the manifestations that would warrant follow-up imaging. MATERIALS AND METHODS:Two neuroradiologists retrospectively reviewed CT angiography (CTA), MR imaging, and plain film studies related to the head and neck in 25 patients ranging from 1 to 55 years of age, all of whom had positive genetic testing and clinical characteristics of LDS. Arterial tortuosity was evaluated by subjective assessment of 2D and 3D volumetric CTA and MR angiography data. Craniosynostosis and spinal manifestations were assessed by using plain films and CT images. MR images mostly of the head were reviewed for associated findings such as hydrocephalus, Chiari malformation, etc. Clinical manifestations were collated from the electronic patient record. RESULTS:All patients had extreme arterial tortuosity, which is characteristic of this syndrome. Thirteen patients had scoliosis, 12 had craniosynostosis, 8 had intracranial aneurysms, 6 had spinal instability, 3 had dissections of the carotid and vertebrobasilar arteries, 3 had hydrocephalus, 4 had dural ectasia, 2 had a Chiari malformation, and 1 had intracranial hemorrhage as a complication of vascular dissection. CONCLUSIONS:Significant neuroradiologic manifestations are associated with LDS, predominantly arterial tortuosity. Most of the patients in this series were young and, therefore, may require serial CTA monitoring for development of intra- and extracranial dissections and aneurysms, on the basis of the fact that most of the patients with pseudoaneurysms and dissection were older at the time of imaging. Other findings of LDS such as craniosynostosis, Chiari malformation, and spinal instability may also need to be addressed.

Dataset Information

Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment?

Publications

Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment?

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