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ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailability regulation

Nature Genetics volume 40, pages 1119–1123 (2008)Cite this article

Abstract

Geleophysic dysplasia is an autosomal recessive disorder characterized by short stature, brachydactyly, thick skin and cardiac valvular anomalies often responsible for an early death. Studying six geleophysic dysplasia families, we first mapped the underlying gene to chromosome 9q34.2 and identified five distinct nonsense and missense mutations in ADAMTSL2 (a disintegrin and metalloproteinase with thrombospondin repeats–like 2), which encodes a secreted glycoprotein of unknown function. Functional studies in HEK293 cells showed that ADAMTSL2 mutations lead to reduced secretion of the mutated proteins, possibly owing to the misfolding of ADAMTSL2. A yeast two-hybrid screen showed that ADAMTSL2 interacts with latent TGF-β–binding protein 1. In addition, we observed a significant increase in total and active TGF-β in the culture medium as well as nuclear localization of phosphorylated SMAD2 in fibroblasts from individuals with geleophysic dysplasia. These data suggest that ADAMTSL2 mutations may lead to a dysregulation of TGF-β signaling and may be the underlying mechanism of geleophysic dysplasia.

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Figure 1: Clinical and radiological manifestations of geleophysic dysplasia in individual 3.
Figure 2: Genetic mapping of the locus involved in geleophysic dysplasia.
Figure 3: In situ hybridization analysis of ADAMTSL2 mRNA expression in a human fetus at 35 weeks of gestation.
Figure 4: Functional consequences of ADAMTSL2 mutations.
Figure 5: Analysis of TGF-β signalling pathway in geleophysic dysplasia fibroblasts.

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References

  1. Spranger, J.W., Gilbert, E.F., Tuffli, G.A., Rossiter, F.P. & Opitz, J.M. Geleophysic dwarfism–a “focal” mucopolysaccharidosis? Lancet 2, 97–98 (1971).

    Article  CAS  PubMed  Google Scholar 

  2. Pontz, B.F. et al. Clinical and ultrastructural findings in three patients with geleophysic dysplasia. Am. J. Med. Genet. 63, 50–54 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Shohat, M. et al. Geleophysic dysplasia: a storage disorder affecting the skin, bone, liver, heart, and trachea. J. Pediatr. 117, 227–232 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Apte, S.S. A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs: the ADAMTS family. Int. J. Biochem. Cell Biol. 36, 981–985 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Hirohata, S. et al. Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix. J. Biol. Chem. 277, 12182–12189 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Hall, N.G., Klenotic, P., Anand-Apte, B. & Apte, S.S. ADAMTSL-3/punctin-2, a novel glycoprotein in extracellular matrix related to the ADAMTS family of metalloproteases. Matrix Biol. 22, 501–510 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Koo, B.H. et al. ADAMTS-like 2 (ADAMTSL2) is a secreted glycoprotein that is widely expressed during mouse embryogenesis and is regulated during skeletal myogenesis. Matrix Biol. 26, 431–441 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Annes, J.P., Munger, J.S. & Rifkin, D.B. Making sense of latent TGFβ activation. J. Cell Sci. 116, 217–224 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Sinha, S., Nevett, C., Shuttleworth, C.A. & Kielty, C.M. Cellular and extracellular biology of the latent transforming growth factor-β binding proteins. Matrix Biol. 17, 529–545 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Isogai, Z. et al. Latent transforming growth factor β-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J. Biol. Chem. 278, 2750–2757 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. ten Dijke, P. & Arthur, H.M. Extracellular control of TGFβ signalling in vascular development and disease. Nat. Rev. Mol. Cell Biol. 8, 857–869 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Ge, G. & Greenspan, D.S. BMP1 controls TGFβ1 activation via cleavage of latent TGFβ-binding protein. J. Cell Biol. 175, 111–120 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Collod-Beroud, G. & Boileau, C. Marfan syndrome in the third millennium. Eur. J. Hum. Genet. 10, 673–681 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Loeys, B.L. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37, 275–281 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Kinoshita, A. et al. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat. Genet. 26, 19–20 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Neptune, E.R. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407–411 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Jones, K.B. et al. Toward an understanding of dural ectasia: a light microscopy study in a murine model of Marfan syndrome. Spine 30, 291–293 (2005).

    Article  PubMed  Google Scholar 

  18. Gordon, K.J. & Blobe, G.C. Role of transforming growth factor-β superfamily signaling pathways in human disease. Biochim. Biophys. Acta 1782, 197–228 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Wang, L.W. et al. O-fucosylation of thrombospondin type 1 repeats in ADAMTS-like-1/punctin-1 regulates secretion: implications for the ADAMTS superfamily. J. Biol. Chem. 282, 17024–17031 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Abbaszade, I. et al. Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J. Biol. Chem. 274, 23443–23450 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Kazusa DNA Research Institute for providing the KIAA0605 cDNA. We thank J. Martinovic for her help. We also thank T. Arai and M. Papouin. The work presented here was supported by French National Research Agency (ANR) award R06215KS (to V.C.-D.), the Medical Research Foundation (FRM, to C.L.G.), US National Institutes of Health (NIH) award AR53890 (to S.S.A.), NIH award GM71679 (to D.S.G.) and NIH award HD22657 (to D.K.).

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Author notes

  1. Fanny Morice-Picard and Nathalie Dagoneau: These authors contributed equally to this work.

Authors and Affiliations

  1. Département de Génétique, Unité INSERM U781, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, 75015, France

    Carine Le Goff, Fanny Morice-Picard, Nathalie Dagoneau, Claire Perrot, Martine Le Merrer, Arnold Munnich & Valérie Cormier-Daire

  2. Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, 44195, Ohio, USA

    Lauren W Wang & Suneel S Apte

  3. Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, LS29JT, UK

    Yanick J Crow

  4. Clinique Paofaï, Fare Tony, Papeete, Tahiti

    Florence Bauer

  5. Département de Génétique, Hôpital de Hautepierre, Strasbourg, 67000, France

    Elisabeth Flori

  6. CNRS UPRES 3410, Faculté de Médecine, Hôpital Avicennes, Bobigny, 93000, France

    Catherine Prost-Squarcioni

  7. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA

    Deborah Krakow

  8. Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, 53706, Wisconsin, USA

    Gaoxiang Ge & Daniel S Greenspan

  9. Service de Cardiologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, 75015, France

    Damien Bonnet

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Contributions

C.L.G. designed the experiments; performed in situ hybridization, protein blot analysis (ADAMTSL2 and SMAD2), TGF-β assays and immunocytochemistry and wrote the manuscript. F.M.-P. and N.D. performed the sequence analysis. L.W.W. performed coimmunoprecipitation studies. C.P., Y.J.C., F.B., E.F., D.K., D.B. and M.L.M. provided clinical data; C.P.-S. performed electron microscopy analysis. G.G. and D.S.G. cloned expression LTBP-1 constructs. A.M. and S.S.A. wrote the manuscript. V.C.-D. provided clinical data, designed the experiments, oversaw all aspects of the research and wrote the manuscript.

Corresponding author

Correspondence to Valérie Cormier-Daire.

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Le Goff, C., Morice-Picard, F., Dagoneau, N. et al. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailability regulation. Nat Genet 40, 1119–1123 (2008). https://doi.org/10.1038/ng.199

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