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Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia.

Authors
  • Chen, Wuyan1
  • Perritt, Ashley F2
  • Morissette, Rachel2
  • Dreiling, Jennifer L3
  • Bohn, Markus-Frederik4
  • Mallappa, Ashwini2
  • Xu, Zhi5
  • Quezado, Martha3
  • Merke, Deborah P2, 6
  • 1 PreventionGenetics, Marshfield, Wisconsin.
  • 2 National Institutes of Health Clinical Center, Bethesda, Maryland.
  • 3 Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland.
  • 4 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California.
  • 5 National Institutes of Health, , National Institute on Aging, Baltimore, Maryland.
  • 6 The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Sep 01, 2016
Volume
37
Issue
9
Pages
893–897
Identifiers
DOI: 10.1002/humu.23028
PMID: 27297501
Source
Medline
Keywords
License
Unknown

Abstract

Some variants that cause autosomal-recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers-Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21-hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin-X, an extracellular matrix protein. Two types of CAH tenascin-X (CAH-X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH-X CH-1 has a TNXB exon 35 120-bp deletion resulting in haploinsufficiency, and CAH-X CH-2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant-negative effect. We present here three patients with biallelic CAH-X and identify a novel dominant-negative chimera termed CAH-X CH-3. Compared with monoallelic CAH-X, biallelic CAH-X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin-X function and computational data linking the type of TNXB variant to disease severity.

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