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Tenascin-X: a Causative Gene of Classical-Like EDS

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Tenascin-X: a Causative Gene of Classical-Like EDS Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Tenascin-X: a causative gene of classical-like EDS Ken-ichi Matsumoto Shimane University Classification of Ehlers-Danlos syndrome Inheritance EDS subtype Abbreviation Prevalence Protein Gene pattern 1 Classical cEDS 1/20 000 AD Type V collagen COL5A1/COL5A2 Tenascin-Tenascin-X (Complete 2 clEDS TNXBTNXB Classical-likeClassical-like clEDS 24 ARAR deficiency)deficiency) 3 Cardiac-valvular cvEDS 4 AR Type I collagen COL1A1 4 Vascular vEDS 1/50 000-250 000 AD Type III collagen COL3A1 5 Hypermobile hEDS 1/5000-20 000 AD Unknown Unknown 6 Arthrochalasia aEDS 49 AD Type I collagen COL1A1/COL1A2 7 Dermatosparaxis dEDS 8 AR ADAMTS-2 ADAMTS2 Lysyl hydroxylase-1, 8 Kyphoscolitotic kEDS 1/100 000 AR PLOD1, FKBP22 FKBP14 Brittle Cornea 9 BCS 11 AR ZNF469, PRDM5 ZNF469, PRDM5 syndrome 8 10 Spondylodysplastic spEDS AR b4GalT7, b3GalT6 B4GALT7, B3GALT6 31 11 Musculocontractural mcEDS AR CHST14, DSE CHST14, DSE 12 Myopathic mEDS AD or AR Type XII collagen COL12A1 13 Periodontal pEDS AD C1r, C1s C1R, C1S Malfait F. et al., Am. J. Med. Genet. Part C 175C, 8-26, 2017. Kosho T. et al., Pediatr. Int. 58, 88-99, 2016. All rights reserveD. 1 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Clinical feature of TNX-deficient type EDS (clEDS) Typical clinical feature • Generalized joint hypermobility (with or without (sub)luxations) • Skin hyperextensibility • Easy bruising Other common clinical feature • Foot and hand deformities Piezogenic papules Pes planus Hallux valgus Broad forefeet Brchydactyly Acrogeric skin of hands • Neurological symptoms Muscle weakness Chronic back pain, myalgias, arthralgias Prof. Emiko Ashitaka Severe fatigue l Cardiovascular abnormality (valvular problems) l Gastrointestinal manifestation Dr. Hiroaki Hanafusa In contrast to the classical type EDS (cEDS) Demirdas et al., Clinical Genet. 91, 411-425, 2017. • Inheritance pattern: Autosomal recessive Malfait et al., Am. J. Med. Genet. Part C Semin. • Without atrophic scarring Med. Genet. 175C, 8-26, 2017. Genetic analysis of TNX-deficient patients • A 2 bp deletion (c.3290_3291del) • Two different 30 kb deletions both generating a TNXB/TNXA fusion gene, and pseudogene-derived missense variant [c.12174C>G p.(Cys4058Trp)] • Premature stop codon [c.903del p.(Tyr301*)], [c.12553C>T p.(Arg4185*)], [c.2461C>T p.(Arg821*)], [c.2590C>T p.(Gln864*)] • Splice site mutation [c.7826-1G>C p.(?)], [c.12464-1G>A p.(?)] • A small deletion/insertion [c.107_108delinsA p.(Ala36Aspfs*68] • A pseudogene-derived 120 bp deletion (c.11435_11524+30del) Demirdas et al., Clinical Genet. 91, 411-425, 2017 All rights reserveD. 2 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Tenascin family TNX (ElefteriouValcourt etet al. al. J., CellBiol. Adh.Chem .Migr. 272, 22866 9, 154-22874,-165, 2015.1997) TNC (Chiquet-Ehrismann et al., J. Pathol. 200, 488-499, 2003) TNR (Pesheva et al., ProG. Neurobiol. 61, 465-493, 2000) TNW (SCherberiCh et al., J. Cell SCi. 117, 571-581, 2004) Expression of TNX Reciprocal expression of TNX to TNC Matsumoto et al., J. Cell Biol. 125, 483-493, 1994. All rights reserveD. 3 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Expression of TNX Expression of TNX in E10-12.5 hearts Immunostaining E12.5 Imanaka-Yoshida et al., Differentiation 71, 291-298, 2003. In situ hybridization Property of TNX Modulation of collagen fibril architecture and tissue integrity Normal skin TNX-deficient skin of clEDS patients Bristow J., Am. J. Med. Genet. C Semin. Med. Genet. 139, 24-30, 2005. All rights reserveD. 4 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Property of TNX Interaction of TNX with type I collagen Solid-phase binding assay Col VI - Col I TNX - Col I TNX - Col VI TNX - FN TNX - LN Minamitani et al., Exp. Cell Res. 298, 305-315, 2004. Property of TNX TNX increases the rate and quantity of collagen fibril formation In vitro collagen fibrillogenesis assay Increased quantity TNX control Increased rate Minamitani et al., Exp. Cell Res. 298, 305-315, 2004. All rights reserveD. 5 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Property of TNX Modulation of collagen fibrillogenesis by TNX Larger diameter of collagen fibril in TNX-/- mice Minamitani et al., Exp. Cell Res. 298, 305-315, 2004. Property of TNX Compromised cell adhesion on TNX substrate Cell attachment assay Fujie et al., Biol. Pharm. Bull. 32, 1795-1799, 2009. All rights reserveD. 6 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Property of TNX Compromised cell adhesion on TNX substrate AB Fujie et al., Biol. Pharm. Bull. 32, 1795-1799, 2009. Property of TNX TNX induces p38 MAP kinase activity Fujie et al., Biol. Pharm. Bull. 32, 1795-1799, 2009. All rights reserveD. 7 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Property of TNX Suppression of TNX-Induced cell detachment by knocking down p38a MAP kinase expression Fujie et al., Biol. Pharm. Bull. 32, 1795-1799, 2009. Collagen gel contraction containing TNX-deficient MEFs Property of TNX Hashimoto et al., Exp. Cell Res. 363, 102-113, 2018. All rights reserveD. 8 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Effect of MMP inhibitors on collagen gel contraction Property of TNX Hashimoto et al., Exp. Cell Res. 363, 102-113, 2018. Property of TNX Effects of TNX absence on proliferation of MEFs in collagen gels Hashimoto et al., Exp. Cell Res. 363, 102-113, 2018. All rights reserveD. 9 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Property of TNX Effects of TNX absence on migration of MEFs in collagen gels Hashimoto et al., Exp. Cell Res. 363, 102-113, 2018. Property of TNX Effect of TNX absence on the formation of filopodia-like protrusions of MEFs cultured in contracted collagen gels Hashimoto et al., Exp. Cell Res. 363, 102-113, 2018. All rights reserveD. 10 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Property of TNX Screening of TNX-binding proteins Ikuta et al., Genes Cells 5, 913-928, 2000. Yeast two-hybrid assay Property of TNX Interaction of TNX with VEGF-B F-TNX F-TNX HA- HA- VEGF-B167 VEGF-B186 IP: a-Flag WB: a-HA IP: a-Flag F-TNX WB: a-HA T7- VEGF-A164 IP: a-Flag WB: a-T7 Ikuta et al., Genes Cells 5, 913-928, 2000. Co-immunoprecipitaion assay All rights reserveD. 11 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Property of TNX Endothelial cell proliferation by VEGF-B in combination with TNX HH Bovine HH endothelial cell Ikuta et al., Genes Cells 5, 913-928, 2000. Property of TNX Stimulation of the autophosphorylation in VEGFR-1 by VEGF-B with TNX Ikuta et al., Genes Cells 5, 913-928, 2000. All rights reserveD. 12 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management TGF-b activation by the FBG-like domain of TNX Property of TNX a11 b1 Alcaraz et al., J. Cell Biol. 205, 409-428, 2014. Valcourt et al., Cell Adh. Migr. 9, 154-165, 2015. Involvement of tenascin-X in osteoclast maturation All rights reserveD. 13 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Osteoblast and osteoclast lineages for bone metabolism MSC HSC MSC: mesencHymal stem cell HSC: Hematopoietic stem cell dendritic cell pre-adipocyte myeloid precursor pre-osteoblast adipocyte macropHage pre-osteoclast RANKL osteoblast RANK osteoclast osteocyte network Ikeda K. et al. J Biochem: 159, 1-8, 2016. Histological analysis of femur WT KO Decrease in Femoral distal end trabecular bone in TNX-KO mice WT KO Decrease in cortical Femoral shaft bone thickness in TNX-KO mice. Scale bars, 500 μm Kajitani et al., Biochem. Biophys. TNX-KO mice exhibit lower bone mass. Res. Commun. 512, 659-664, 2019. All rights reserveD. 14 Scientific Meeting on the Rarer Types of 18 November 2019 EDS: From Genetics to Management Bone morphology analysis of trabecular bone TrabecularTrabecular bone bone mineral mineral density density TrabecularTrabecular percent percent bone bone volume volume WT KO 0.4 20 ) * 3 * 0.3 * 15 * 0.2 10 ** 4 w WT 0.1 KO 5 BV/TV (%) BV/TV BMD (g/cm BMD 0 0 4 w 10 w 8 m 4 w 10 w 8 m 10 w TrabecularTrabecular thickness thickness TrabecularTrabecular separation separation 80 400 * ) * 60 * 300 * μm ( 40 200 20 100 Tb.Th (μm) Tb.Th Tb.SP 0 0 8 m 4 w 10 w 8 m 4 w 10 w 8 m Scale bars, 500 μm TrabecularTrabecular number number 2.5 * ) 1 - 2 1.5 ** * (mm 1 0.5 Tb.N 0 means ±SE , n=5 4 w 10 w 8 m *P< 0.05, **P<0.005 The bone mass and bone mineral density (BMD) of trabecular bone are significantly lower in Tnxb-KO mice than those of age-matched WT mice. Kajitani et al., Biochem. Biophys. Res. Commun. 512, 659-664, 2019. Analysis of osteoblast differentiation Tnxb expression during osteogenic differentiation d0 d3 d10 WTKO WT KO WT KO Tnxb Actb Alizarin red S staining WT KO 0.06 0.04 0.02 OD415 (nm) 0 WT KO means±SE, n=5 Osteoblast differentiation is not affected by TNX deficiency. Kajitani et al., Biochem.
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