Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia
Open accessAbstract
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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CAH-X CH-1 does not produce structural changes in the TNX protein but reduces TNX expression, in contrast to the altered production of TNX proteins from both CAH-X CH-2 and CAH-X CH-3.
“CAH-X CH-1 does not produce structural changes in the TNX protein but, rather, reduces the TNX expression, this being in contrast to the altered production of TNX proteins from both CAH-X CH-2 and CAH-X CH-3 [35].”
From Salt-wasting congenital adrenal hyperplasia phenotype as a result of the TNXA/TNXB chimera 1 (CAH-X CH-1) and the pathogenic IVS2-13A/C > G in CYP21A2 gene (2023) · cites this paper as [35]
The passage on the three chimeras (section labeled Abstract; page unavailable) says CH-1 causes haploinsufficiency, while CH-2 alters TNX structure without changing its expression. It presents CH-3 structural changes as likely, based on the variant cluster, rather than establishing the claim’s unqualified assertion that altered TNX protein is produced. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCAH-X CH-3 is characterized by a cluster of three mutations (p.Arg4073His, p.Asp4172Asn, and p.Ser4175Asn) derived from the TNXA pseudogene.
“CAH-X CH-2 and CAH-X CH-3 types are less frequently found in CAH patients, with CAH-X CH-2 being characterized by the variant c.12174C > G (p.Cys4058Trp), which derives from the TNXA pseudogene [7], and CAH-X CH-3, being characterized by a cluster of three mutations (p.Arg4073His, p.Asp4172Asn, and p.Ser4175Asn) also derived from the TNXA pseudogene [35].”
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- Authors
- Chen, W., Perritt, A. F., Morissette, R., Dreiling, J. L., Bohn, M.-F., Mallappa, A., Xu, Z., Quezado, M., & Merke, D. P.
- Affiliations
- PreventionGenetics; Marshfield Wisconsin
- National Institutes of Health (US)
- National Cancer Institute (US)
- University of California, San Francisco (US)
- National Institutes of Health; , National Institute on Aging; Baltimore Maryland
- Corresponding author
- Merke, Deborah P.
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2016-07-08
- Volume
- 37
- Issue
- 9
- Pages
- 893-897
- ISSN
- 1059-7794 (ISSN-L)
- PMC
- PMC4983206
- OpenAlex
- W2438303517
- Cited by
- 45
- References
- 21
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 3
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health Clinical Center
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Cancer Institute
- National Institute on Aging
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- Ehlers-Danlos syndrome, congenital adrenal hyperplasia, tenascin-X, CYP21A2, dominant negative effect, haploinsufficiency, disease severity, extracellular matrix proteins, genotype-phenotype correlation
- MeSH terms
- Fibrillin-1, Adolescent, Adrenal Hyperplasia, Congenital, Adult, Alleles, Collagen, Ehlers-Danlos Syndrome, Female, Humans, Male, Pedigree, Steroid 21-Hydroxylase, Gene Deletion, Tenascin, Adipokines, Young Adult
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