Tenascin-X (TNX) is an extracellular matrix protein expressed in developing connective tissues. The TNX and 21-hydroxylase (CYP21B) genes overlap in the class III region of the MHC. A partially duplicated TNX gene (XA) and the overlapping CYP21A pseudogene are closely linked. Recently, we were referred a 26 yo male with congenital adrenal hyperplasia due to CYP21B deficiency and Ehlers-Danlos syndrome (EDS). EDS is a connective tissue disorder consisting of hypermobile joints, hyperextensible skin and easy bruising. To investigate if this patient's condition was due to a contiguous gene syndrome involving TNX and CYP21B, we cultured skin fibroblasts from the patient, his parents and normal controls. Western blots of fibroblast conditioned medium (concentrated using 3 independent purification methods) showed TNX expression in both parents and normal controls, but not in any sample from the proband. Blotting of proteins extracted directly from a biopsy of the proband's skin also failed to show TNX expression and RNase protection assays on the proband's fibroblast RNA showed no TNX transcript. Because 20% of CYP21B deficient alleles carry a 30 kb deletion due to unequal crossover between CYP21A and B, we postulated that crossover between XA and TNX deleted CYP21B and produced a mutant TNX/XA fusion gene. We paired a TNX-specific sense primer with TNX or XA-specific antisense primer in PCR experiments. The TNX-specific pair generated a 2.4 kb product in all family members while the TNX/XA primer pair, normally 32 kb apart, generated a 2.4 kb TNX/XA fusion product in the proband, father and a sister. This novel deletion was confirmed by standard and pulsed-field Southern analysis. Southern blotting also demonstrated a maternal CYP21 gene conversion, accounting for the proband's CYP21B deficiency, but his maternal TNX mutation remains unknown. This study demonstrates that TNX deficiency is a cause of Ehlers-Danlos Syndrome, and that TNX has unique functions in connective tissue development and integrity.
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Burch, G., Gong, Y., Liu, W. et al. Human Tenascin-X Deficiency is a Cause of Ehlers-Danlos Syndrome. • 595. Pediatr Res 41 (Suppl 4), 102 (1997). https://doi.org/10.1203/00006450-199704001-00615
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DOI: https://doi.org/10.1203/00006450-199704001-00615