Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia.
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.
PreventionGenetics, Marshfield, Wisconsin.
Wuyan
W
Chen
National Institutes of Health Clinical Center, Bethesda, Maryland.
Ashley F
AF
Perritt
National Institutes of Health Clinical Center, Bethesda, Maryland.
Rachel
R
Morissette
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland.
Jennifer L
JL
Dreiling
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California.
Markus-Frederik
MF
Bohn
National Institutes of Health Clinical Center, Bethesda, Maryland.
Ashwini
A
Mallappa
National Institutes of Health, , National Institute on Aging, Baltimore, Maryland.
Zhi
Z
Xu
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland.
Martha
M
Quezado
National Institutes of Health Clinical Center, Bethesda, Maryland.|The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
Deborah P
DP
Merke
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D003094:Collagen / Q000378:metabolism; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000071838:Fibrillin-1 / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008297:Male; D010375:Pedigree; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D019063:Tenascin / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D054392:Adipokines
D003094:Collagen; D000071838:Fibrillin-1; D013255:Steroid 21-Hydroxylase; D019063:Tenascin; C000605722:FBN1 protein, human; D054392:Adipokines; C081865:tenascin X; C531510:CYP21A2 protein, human
CAH-X; Ehlers-Danlos syndrome; biallelic; congenital adrenal hyperplasia; tenascin-X