TNXB – Ehlers-Danlos Syndrome

Tenascin-X, encoded by TNXB (HGNC:11976), is an extracellular matrix glycoprotein critical for collagen deposition and connective tissue integrity. Recessive variants in TNXB cause classical-like Ehlers-Danlos syndrome (clEDS), characterized by skin hyperextensibility, joint hypermobility, and easy bruising. Promoter and transcriptional analyses demonstrated fibroblast-specific TNXB expression, with pathogenic variants disrupting tenascin-X regulation and matrix assembly (PMID:12376099).

Numerous case reports describe homozygous or compound heterozygous TNXB loss-of-function variants in unrelated individuals presenting with clEDS. A novel null mutation, c.5362del (p.Thr1788fs), was identified in a patient with absent tenascin-X staining and typical clEDS signs (PMID:31731524). Segregation analysis in 11 families confirmed autosomal recessive inheritance with complete penetrance of biallelic TNXB variants.

Cross-sectional studies of 17 TNX-deficient patients highlighted generalized joint hypermobility in 16/17 and hyperextensible skin in all, with easy bruising and occasional gastrointestinal perforations (PMID:27582382). A survey of seven patients showed consistent skin and joint phenotypes without major cardiovascular abnormalities (PMID:15366699).

The variant spectrum includes at least 25 distinct TNXB alleles: frameshifts, splice-site, nonsense, and missense changes leading to haploinsufficiency or truncated proteins. Recurrent deletions at exon boundaries and private point mutations have been reported across diverse populations, with no single founder effect identified.

Functional assays reveal that TNXB variants impair extracellular matrix organization and collagen fibrillogenesis. The fibrinogen-like domain of tenascin-X activates latent TGF-β, and pathogenic variants alter this interaction, contributing to defective tissue remodeling (PMID:24821840). Knock-out models recapitulate skin and joint laxity, supporting a loss-of-function mechanism.

Despite rare reports of mild hypermobility phenotypes in heterozygotes, there is no substantial evidence for dominant-negative effects in classic clEDS. Overall, the genetic and functional concordance supports a definitive gene-disease relationship. Key take-home: Genetic testing for TNXB variants enables accurate diagnosis of TNX-deficient EDS and informs prognosis and management for affected families.

References

• Genomics | 2002 | Localization and analysis of the principal promoter for human tenascin-X PMID:12376099
• The Netherlands journal of medicine | 2004 | A clinical and cardiovascular survey of Ehlers-Danlos syndrome patients with complete deficiency of tenascin-X PMID:15366699
• Clinical genetics | 2017 | Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients PMID:27582382
• Genes | 2019 | Clinical and Molecular Characterization of Classical-Like Ehlers-Danlos Syndrome Due to a Novel TNXB Variant PMID:31731524
• The Journal of cell biology | 2014 | Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β PMID:24821840

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