title: Transforming growth factor-β (TGF-β) pathway abnormalities in tenascin-X deficiency associated with CAH-X syndrome.
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.
authors.affiliation: 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.
authors.forename: Rachel
authors.initials: R
authors.lastname: Morissette
authors.affiliation: 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.
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
authors.affiliation: 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.
authors.forename: Nazli B
authors.initials: NB
authors.lastname: McDonnell
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019063:Tenascin / Q000172:deficiency*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000097:blood / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000096:biosynthesis; D055815:Young Adult
chemical_list: D019485:Bone Morphogenetic Proteins; D019063:Tenascin; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; C081865:tenascin X; D053509:Matrix Metalloproteinase 13
keywords: CAH; Cardiac abnormalities; Cleft palate; TGF-β pathway; Tenascin-X deficiency