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Eur J Med Genet. 2014 Feb;57(2-3):95-102. doi: 10.1016/j.ejmg.2013.12.004. Epub 2013 Dec 28.

Transforming growth factor-β (TGF-β) pathway abnormalities in tenascin-X deficiency associated with CAH-X syndrome.

Author information

1
National Institutes of Health, National Institute on Aging, NIA Clinical Unit, 5th Floor, 3001 S. Hanover Street, Baltimore, MD 21225, USA; The National Institutes of Health, Clinical Center, Bethesda, MD, USA. Electronic address: morissetter@mail.nih.gov.
2
The National Institutes of Health, Clinical Center, Bethesda, MD, USA; The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
3
National Institutes of Health, National Institute on Aging, NIA Clinical Unit, 5th Floor, 3001 S. Hanover Street, Baltimore, MD 21225, USA. Electronic address: nazli.mcdonnell@gmail.com.

Abstract

Patients with congenital adrenal hyperplasia (CAH) with tenascin-X deficiency (CAH-X syndrome) have both endocrine imbalances and characteristic Ehlers Danlos syndrome phenotypes. Unlike other subtypes, tenascin-X-related Ehlers Danlos syndrome is caused by an extracellular matrix protein deficiency rather than a defect in fibrillar collagen or a collagen-modifying enzyme, and the understanding of the disease mechanisms is limited. We hypothesized that transforming growth factor-β pathway dysregulation may, in part, be responsible for connective tissue phenotypes observed in CAH-X, due to this pathway's known role in connective tissue disorders. Fibroblasts and direct tissue from human skin biopsies from CAH-X probands and age- and sex-matched controls were screened for transforming growth factor-β biomarkers known to be dysregulated in other hereditary disorders of connective tissue. In CAH-X fibroblast lines and dermal tissue, pSmad1/5/8 was significantly upregulated compared to controls, suggesting involvement of the bone morphogenetic protein pathway. Additionally, CAH-X samples compared to controls exhibited significant increases in fibroblast-secreted TGF-β3, a cytokine important in secondary palatal development, and in plasma TGF-β2, a cytokine involved in cardiac function and development, as well as palatogenesis. Finally, MMP-13, a matrix metalloproteinase important in secondary palate formation and tissue remodeling, had significantly increased mRNA and protein expression in CAH-X fibroblasts and direct tissue. Collectively, these results demonstrate that patients with CAH-X syndrome exhibit increased expression of several transforming growth factor-β biomarkers and provide a novel link between this signaling pathway and the connective tissue dysplasia phenotypes associated with tenascin-X deficiency.

KEYWORDS:

CAH; Cardiac abnormalities; Cleft palate; TGF-β pathway; Tenascin-X deficiency

PMID:
24380766
PMCID:
PMC3972366
DOI:
10.1016/j.ejmg.2013.12.004
[Indexed for MEDLINE]
Free PMC Article

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