The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition
Abstract
Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme, we suggested that tenascin-X might regulate collagen synthesis or deposition. To test this hypothesis, we inactivated Tnxb in mice. Tnxb-/- mice showed progressive skin hyperextensibility, similar to individuals with Ehlers-Danlos syndrome. Biomechanical testing confirmed increased deformability and reduced tensile strength of their skin. The skin of Tnxb-/- mice was histologically normal, but its collagen content was significantly reduced. At the ultrastructural level, collagen fibrils of Tnxb-/- mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb-/- and wildtype cells was similar, Tnxb-/- fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“TNXB encodes tenascin-X, which is highly expressed in connective tissues. It is essential in the maintenance of the integrity of the extracellular matrix by regulating the collagen fi bril deposition, in which defects lead to EDS, a hereditary connective tissue disorder. 21”
From High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia. (2019) · cites this paper as [21]
Citations
Cites
A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency
Schalkwijk, J., Zweers, M. C., Steijlen, P. M., Dean, W. B., Taylor, G., van Vlijmen, I. M., van Haren, B., Miller, W. L., & Bristow, J. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa002939 · Cited by 391
Self-citationTenascin-X deficiency is associated with Ehlers-Danlos syndrome
Burch, G. H., Gong, Y., Liu, W., Dettman, R. W., Curry, C. J., Smith, L., Miller, W. L., & Bristow, J. (1997) · Nature Genetics · doi:10.1038/ng0997-104 · Cited by 366
Self-citationTumour invasion and metastasis are promoted in mice deficient in tenascin‐X
Matsumoto, K., Takayama, N., Ohnishi, J., Ohnishi, E., Shirayoshi, Y., Nakatsuji, N., & Ariga, H. (2001) · Genes to Cells · doi:10.1046/j.1365-2443.2001.00482.x · Cited by 81
Flagged first, then by citations
Research works printed but not linked: 26
- Bristow, J., Tee, M.K., Gitelman, S.E., Mellon, S.H. & Miller, W.L. Tenascin-X: a novel extracellular matrix protein encoded by the human XB gene overlapping P450c21B. J. Cell Biol. 122, 265–278 (1993). · DOI · Paper page
- Lethias, C., DesCollonges, Y., Boutillon, M. & Garrone, R. Flexilin: a new extracellular matrix glycoprotein localized on collagen fibrils. Matrix Biol. 15, 11–19 (1996). · DOI
- Matsumoto, K., Saga, Y., Ikemura, T., Sakakura, T. & Chiquet-Ehrismann, R. The distribution of tenascin-X is distinct and often reciprocal to that of tenascin-C. J. Cell Biol. 125, 483–493 (1994). · DOI
- Beighton, P., De Paepe, A., Steinmann, B., Tsipouras, P. & Wenstrup, R.J. Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers–Danlos National Foundation (USA) and Ehlers–Danlos Support Group (UK). Am. J. Med. Genet. 77, 31–37 (1998). · DOI · Paper page
- Burrows, N. et al. A point mutation in an intronic branch site results in aberrant splicing of COL5A1 and in Ehlers–Danlos syndrome type II in two British families. Am. J. Hum. Genet. 63, 390–398 (1998). · DOI
- De Paepe, A., Nuytinck, L., Hausser, I., Anton-Lamprecht, I. & Naeyaert, J.M. Mutations in the COL5A1 gene are causal in the Ehlers–Danlos syndromes I and II. Am. J. Hum. Genet. 60, 547–554 (1997).
- Eyre, D.R., Shapiro, F.D. & Aldridge, J.F. A heterozygous collagen defect in a variant of the Ehlers–Danlos syndrome type VII. Evidence for a deleted amino-telopeptide domain in the pro-α 2(I) chain. J. Biol. Chem. 260, 11322–11329 (1985). · DOI
- Hyland, J. et al. A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers–Danlos syndrome type VI. Nature Genet. 2, 228–231 (1992). · DOI
- Smith, L.T., Schwarze, U., Goldstein, J. & Byers, P.H. Mutations in the COL3A1 gene result in the Ehlers–Danlos syndrome type IV and alterations in the size and distribution of the major collagen fibrils of the dermis. J. Invest. Dermatol. 108, 241–247 (1997). · DOI · Paper page
- Smith, L.T. et al. Human dermatosparaxis: a form of Ehlers–Danlos syndrome that results from failure to remove the amino-terminal propeptide of type I procollagen. Am. J. Hum. Genet. 51, 235–244 (1992).
- Toriello, H.V. et al. A translocation interrupts the COL5A1 gene in a patient with Ehlers–Danlos syndrome and hypomelanosis of Ito. Nature Genet. 13, 361–365 (1996). · DOI
- Wenstrup, R.J., Langland, G.T., Willing, M.C., D'Souza, V.N. & Cole, W.G. A splice-junction mutation in the region of COL5A1 that codes for the carboxyl propeptide of pro α 1(V) chains results in the gravis form of the Ehlers–Danlos syndrome (type I). Hum. Mol. Genet. 5, 1733–1736 (1996). · DOI
- Mao, J.R. & Bristow, J. The Ehlers-Danlos syndrome: on beyond collagens. J. Clin. Invest. 107, 1063–1069 (2001). · DOI · Paper page
- Morel, Y., Bristow, J., Gitelman, S.E. & Miller, W.L. Transcript encoded on the opposite strand of the human steroid 21-hydroxylase/complement component C4 gene locus. Proc. Natl Acad. Sci. USA 86, 6582–6586 (1989). · DOI · Paper page
- Fung, Y. Biomechanics: Mechanical Properties of Living Tissues 259–260 (Springer-Verlag, New York, 1990). · DOI
- Daly, C. Biomechanical properties of dermis. J. Invest. Dermatol. 79 (suppl.), 17S–20S (1982). · DOI
- Byers, P.H. in The Metabolic and Molecular Bases of Inherited Disease Vol. 3 (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 4029–4077 (McGraw-Hill, New York, 1995).
- Vogel, A., Holbrook, K.A., Steinmann, B., Gitzelmann, R. & Byers, P.H. Abnormal collagen fibril structure in the gravis form (type I) of Ehlers–Danlos syndrome. Lab. Invest. 40, 201–206 (1979).
- Burch, G.H., Bedolli, M.A., McDonough, S., Rosenthal, S.M. & Bristow, J. Embryonic expression of tenascin-X suggest a role in limb, muscle, and heart development. Develop. Dynam. 203, 491–504 (1995). · DOI · Paper page
- Bonadio, J. et al. Transgenic mouse model of the mild dominant form of osteogenesis imperfecta. Proc. Natl Acad. Sci. USA 18, 7145–7149 (1990). · DOI
- Botas, C. et al. Altered surfactant homeostasis and alveolar type II cell morphology in mice lacking surfactant protein D. Proc. Natl Acad. Sci. USA 95, 11869–11874 (1998). · DOI
- Cheng, P. An improved method for the determination of hydroxyproline in rat skin. J. Invest. Derm. 53, 112–115 (1969). · DOI
- Coats, W., Cheung, D., Han, B., Currier, J. & Faxon, D. Balloon angioplasty significantly increases collagen content but does not alter collagen subtype I/III ratios in the atherosclerotic rabbit iliac model. J. Mol. Cell. Cardiol. 28, 441–446 (1996). · DOI
- Bateman, J., Chan, D., Mascara, T., Rogers, J. & Cole, W. Collagen defects in lethal perinatal osteogenesis imperfecta. Biochem. J. 240, 699–708 (1986). · DOI
- Barsh, G., David, K. & Byers, P. Type I osteogenesis imperfecta: a nonfunctional allele for proα1(I) chains of type I procollagen. Proc. Natl Acad. Sci. USA 79, 3838 (1982). · DOI
- Saga, Y., Yagi, T., Ikawa, Y., Sakakura, T. & Aizawa, S. Mice develop normally without tenascin. Genes Develop. 6, 1821–1831 (1992). · DOI
Cited by
Sorted by citations
Items 201–231 of 231
Primary Disorders of Connective Tissue
Cole, W. G., & Mäkitie, O. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-24145-8.00054-5 · Cited by 6
Ginocchio, S., McCabe, M. C., Flockton, A. R., Gumina, D. L., Hansen, K. C., Ji, S., & Su, E. J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211179 · Cited by 1
“…the most significantly different iECM protein between groups, was lower in FGR a/r CDM. Low levels of TNXB have been implicated in disorganized collagen fibrils and in classical-like Ehlers–Danlos syndrome, likely through its role in regulating collagen fibrillogenesis and fibril spacing [70–73].”
Pediatric pulmonary hemorrhage observed in non-vascular and vascular Ehlers–Danlos syndrome
Yang, R., Haiming, Y., Shen, C., Yao, X., Liu, J., Li, H., & Zhao, S. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-025-03858-2 · Cited by 1
Radler, C. N., Wang, T., LeGate, J. F., Crone, L., Deo, P., Wortley, J., Moore, P., Bryant, G., Smitherman, K., & Sathyamoorthy, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136535 · Cited by 2
“Additionally, skin tissue from TNXB -deficient mice demonstrates reduced collagen density in the ECM [60].”
Patra, C., Rayrikar, A., Wagh, G., Kleefeldt, F., Roshanbinfar, K., Cop, F., Nikolic, I., Schmidt, M. H., Acker-Palmer, A., Ergün, S., et al. (2025) · Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease · doi:10.1161/jaha.123.037943 · Cited by 2
van Gurp, J. E., Lechner, R., Micha, D., Maugeri, A., Dulfer, E., van Dijk, F. V., Keszthelyi, D., Malfatti, E., Kubo, A., Voermans, N., et al. (2025) · Clinical and Translational Gastroenterology · doi:10.14309/ctg.0000000000000821 · Cited by 2
“Mao et al (6) showed that de-fi ciency of TNX leads to a reduction in collagen deposition, which may account for the weakening of the extracellular matrix (6).”
Impact of high-intensity interval training on tendon related gene expression in rat Achilles tendon.
Tsuchiya, Y., Takakura, H., Osawa, S., & Izawa, T. (2023) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2023.03.076 · Cited by 2
Genomic Organization of the Mouse Major Histocompatibility Complex
Kumánovics, A. (2007) · Elsevier eBooks · doi:10.1016/b978-012369454-6/50081-9 · Cited by 2
Basement membrane and extracellular matrix molecules in the skin
Tzu, J., Li, J., & Marinkovich, M. (2005) · Advances in developmental biology · doi:10.1016/s1574-3349(05)15004-2 · Cited by 2
Ghosh, A., Horn, P., Samaha, M. K., Kacperski, J., LeCates, S., White, S., Powers, S. W., & Hershey, A. (2023) · Neurology Clinical Practice · doi:10.1212/cpj.0000000000200188 · Cited by 1
Santoreneos, R., Vakulin, C., Ellul, M., Rawlings, L. H., Hardy, T., & Poplawski, N. K. (2022) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.62674 · Cited by 3
“TNXB-protein has been shown to regulate collagen metabolism, specifically reducing the deposition of fibrils independent of collagen synthesis or fibrillogensis, as well as play a critical role in stabilization of fibrillar-collagen matrix (Mao et al., 2002; Minamitani et al., 2004; Veit et al., 2006).”
BackgroundMirza, N., Upadhyaya, S., Mehta, S., Malhotra, S., & Sibal, A. (2020) · Journal of Pediatric Genetics · doi:10.1055/s-0041-1724048 · Cited by 1
Die Ehlers-Danlos-Syndrome mit Schwerpunkt auf dem hypermobilen Typ
Sturm, K., & Bohn, M. (2019) · Journal für Mineralstoffwechsel & Muskuloskelettale Erkrankungen · doi:10.1007/s41970-019-0058-5 · Cited by 1
Progress in the understanding of connective tissue disorders
Wenstrup, R. J. (2005) · doi:10.1002/ajmg.c.30067 · Cited by 1
“The association between tenascin deficiency and the Ehlers– Danlos syndrome was an important step in broadening consideration of disease pathogenesis beyond collagens and their modifying enzymes [Burch et al., 1997; Mao et al., 2002].”
BackgroundВОЗМОЖНОСТИ ЛАБОРАТОРНОЙ ОЦЕНКИ СОСТОЯНИЙ СОЕДИНИТЕЛЬНОЙ ТКАНИ
Березовская, Г. А., & Эмануэль, В. Л. (2015) · The Scientific Notes of the Pavlov University · doi:10.24884/1607-4181-2015-22-2-37-41 · Cited by 1
Byers, P. H. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-383834-6.00161-0 · Cited by 7
The Molecular Basis of Joint Hypermobility
Beighton, P., Grahame, R., & Bird, H. A. (2011) · Springer eBooks · doi:10.1007/978-1-84882-085-2_3 · Cited by 1
Uitto, J., & Ringpfeil, F. (2006) · Humana Press eBooks · doi:10.1007/978-1-59259-963-9_106 · Cited by 1
Aubert, A., Prudova, A., Tang, J. S., Sidhu, J., Adomat, H. H., Stretovych, S.-E., Shen, Y., Richardson, K. C., Ferrari, D. P., Lane, M. D., et al. (2026) · Matrix Biology · doi:10.1016/j.matbio.2026.102054
Turgaliyev, A., Konovalov, R., Borissenko, A., & Riethmacher, D. (2026) · Biomolecules · doi:10.3390/biom16081191
Sumioka, T., Iwanishi, H., Jester, J. V., Joshi, R., Bradford, S. M., Yasuda, S., Miyajima, M., Okada, Y., Matsumoto, K., & Saika, S. (2026) · The Ocular Surface · doi:10.1016/j.jtos.2026.06.013
Hunt, H. L., Biggs, M. A., Goncavles, B. G., & Banerjee, I. A. (2024) · Soft Materials · doi:10.1080/1539445x.2024.2413063 · Cited by 1
“[35,36] Thus, docking studies were carried out with the triple helix region of collagen and with the fibronectin type III (FN III) domain of tenascin-X.”
Burrows, N. (2019) · Wiley eBooks · doi:10.1002/9781119142812.ch93 · Cited by 11
Part 2: The extracellular matrix in undiagnosed connective tissue disease
Stone, L. E., Fegley, M., Pangtey, G., Longo, S., & Nanda, S. (2017) · International Journal of Academic Medicine · doi:10.4103/2455-5568.209846
“X present with normal fibroblast derived collagen synthesis, but abnormal organization into the ECM.”
BackgroundInfluentialChanging Paradigms in Cell Biology: Their Implication and Possible Applications
Godwill, E. A. (2015) · doi:10.4172/2168-9652.1000184
“Tenascin X gene, which overlaps with last exon of the CYP21 gene, is essential in regulation of collagen deposition by dermal fibroblasts and has a causative role in human Ehlers-Danlos syndrome [50].”
BackgroundVoermans, N. C., & Huijing, P. A. (2012) · Elsevier eBooks · doi:10.1016/b978-0-7020-3425-1.00068-4
Charvet, B. (2011) · doi:10.70675/6c540e84z9f89z44ecz84acz8b1e191dc159
“Interestingly, analysis of knock-outmice and patients with Ehlers-Danlos Syndrome, which is characterized by hyperextensible skin and laxity of joints, has revealed that tenascin X is needed for correct collagen fibril deposition and spacing (Burch et al., 1997; Mao et al., 2002).”
Collagen supramolecular structures: Evolution, organization, and biogenesis
Suki, B. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-819716-5.00003-4
Molecular and Cellular Developments in Heart Valve Development and Disease
Anstine, L. J., Baker, A. S., & Lincoln, J. (2018) · Springer eBooks · doi:10.1007/978-3-030-01993-8_9 · Cited by 2
Functional analysis of polymorphisms in asthma genes : TSLP and IL1RL1
Akhabir, L. (2014) · cIRcle (University of British Columbia) · doi:10.14288/1.0166983
Metadata
- Authors
- Mao, J. R., Taylor, G., Dean, W. B., Wagner, D. R., Afzal, V., Lotz, J. C., Rubin, E. M., & Bristow, J.
- Affiliations
- University of California, San Francisco (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Bristow, James
- Venue
- Nature Genetics
- Published
- 2002-03-04
- Volume
- 30
- Issue
- 4
- Pages
- 421-425
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2062321035
- Cited by
- 261
- References
- 0
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 11 · 2021: 16 · 2020: 12 · 2019: 10 · 2018: 10 · 2017: 7 · 2016: 10 · 2015: 14 · 2014: 7 · 2013: 14 · 2012: 13
- FWCI
- 7.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- tenascin-X, TNXB, Ehlers-Danlos syndrome, collagen deposition, type I collagen, dermal fibroblasts, skin hyperextensibility, connective tissue diseases, extracellular matrix, skin biomechanics, knockout mice
- MeSH terms
- Animals, Collagen, Ehlers-Danlos Syndrome, Exons, Fibroblasts, Humans, Male, Microscopy, Electron, Microscopy, Fluorescence, Models, Genetic, Molecular Sequence Data, Mutation, Phenotype, Plasmids, Recombination, Genetic, Skin Physiological Phenomena, Time Factors, Immunoblotting, Mice, Knockout, Tenascin, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
