Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia.

Autor:	Morissette R; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Chen W; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Perritt AF; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Dreiling JL; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Arai AE; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Sachdev V; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Hannoush H; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Mallappa A; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Xu Z; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., McDonnell NB; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Quezado M; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224., Merke DP; Clinical Center (R.M., A.F.P., A.M., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892-1932; PreventionGenetics (W.C.), Marshfield, Wisconsin 54449; Laboratory of Pathology (J.L.D., M.Q.), National Cancer Institute, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; National Heart, Lung, and Blood Institute (A.E.A., V.S., H.H.), Bethesda, Maryland 20892; and National Institute on Aging (Z.X., N.B.M.), National Institutes of Health, Baltimore, Maryland 21224.
Jazyk:	angličtina
Zdroj:	The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2015 Aug; Vol. 100 (8), pp. E1143-52. Date of Electronic Publication: 2015 Jun 15.
DOI:	10.1210/jc.2015-2232
Abstrakt:	Context: The contiguous gene deletion syndrome (CAH-X) was described in a subset (7%) of congenital adrenal hyperplasia (CAH) patients with a TNXA/TNXB chimera, resulting in deletions of CYP21A2, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). This TNXA/TNXB chimera is characterized by a 120-bp deletion in exon 35 and results in TNXB haploinsufficiency, disrupted TGF-β signaling, and an Ehlers Danlos syndrome phenotype. Objective: The objective of the study was to determine the genetic status of TNXB and resulting protein defects in CAH patients with a CAH-X phenotype but not the previously described TNXA/TNXB chimera. Design, Settings, Participants, and Intervention: A total of 246 unrelated CAH patients were screened for TNXB defects. Genetic defects were investigated by Southern blotting, multiplex ligation-dependent probe amplification, Sanger, and next-generation sequencing. Dermal fibroblasts and tissue were used for immunoblotting, immunohistochemical, and coimmunoprecipitation experiments. Main Outcome Measures: The genetic and protein status of tenascin-X in phenotypic CAH-X patients was measured. Results: Seven families harbor a novel TNXB missense variant c.12174C>G (p.C4058W) and a clinical phenotype consistent with hypermobility-type Ehlers Danlos syndrome. Fourteen CAH probands carry previously described TNXA/TNXB chimeras, and seven unrelated patients carry the novel TNXB variant, resulting in a CAH-X prevalence of 8.5%. This highly conserved pseudogene-derived variant in the TNX fibrinogen-like domain is predicted to be deleterious and disulfide bonded, results in reduced dermal elastin and fibrillin-1 staining and altered TGF-β1 binding, and represents a novel TNXA/TNXB chimera. Tenascin-X protein expression was normal in dermal fibroblasts, suggesting a dominant-negative effect. Conclusions: CAH-X syndrome is commonly found in CAH due to 21-hydroxylase deficiency and may result from various etiological mechanisms.
Databáze:	MEDLINE
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