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

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.

• Authors: Wuyan Chen, Ashley F Perritt, Rachel Morissette, Jennifer L Dreiling, Markus-Frederik Bohn, Ashwini Mallappa, Zhi Xu, Martha Quezado, Deborah P Merke
• Journal: Human mutation (Hum Mutat) Vol. 37 Issue 9 Pg. 893-7 (09 2016) ISSN: 1098-1004 [Electronic] United States
• PMID: 27297501 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: © 2016 WILEY PERIODICALS, INC.

Chemical References

• FBN1 protein, human
• Fibrillin-1
• Tenascin
• tenascin X
• Collagen
• CYP21A2 protein, human
• Steroid 21-Hydroxylase

Topics

• Adolescent
• Adrenal Hyperplasia, Congenital (genetics, metabolism)
• Adult
• Alleles
• Collagen (metabolism)
• Ehlers-Danlos Syndrome (genetics, metabolism)
• Female
• Fibrillin-1 (metabolism)
• Gene Deletion
• Humans
• Male
• Pedigree
• Steroid 21-Hydroxylase (genetics)
• Tenascin (genetics, metabolism)
• Young Adult