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Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity

Nature Genetics volume 43, pages 132–137 (2011)Cite this article

Abstract

Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.

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Figure 1: Pleiotropism of SPENCD.
Figure 2: Mutations in ACP5 and their effect on TRAP activity.
Figure 3: Osteopontin deregulation in SPENCD.
Figure 4: TRAP-deficient dendritic cells secrete Th1-polarizing cytokines and show enhanced T cell allostimulatory activity.
Figure 5: Variable serum cytokine patterns in individuals with SPENCD.

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Acknowledgements

We thank our cases and their families for participation in this study. We are also grateful to T. Velten and to the Lausch/Zabel lab for excellent technical assistance and to M. Osawa and H. Katumori, Tokyo, for clinical information. S. Ehl and his group at the Centre for Chronic Immunodeficiency in Freiburg were most helpful in discussing immunological aspects and experimental strategies. This work was made possible by continuous grant support from the Deutsche Forschungsgemeinschaft to E.L. and B.Z. (La 1381/1-3). B.Z. is also supported by the German Bundesministerium für Bildung und Forschung (SKELNET project), and A.S.-F. is supported by the Leenaards Foundation (Lausanne, Switzerland). The paper is dedicated to Céline and Sinai.

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Authors and Affiliations

  1. Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, University of Freiburg, Freiburg, Germany

    Ekkehart Lausch, Jürgen Spranger, Sheila Unger, Bernhard Zabel & Andrea Superti-Furga

  2. Department of Pediatrics II and Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria

    Andreas Janecke

  3. Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Matthias Bros & Stefanie Trojandt

  4. Department of Pediatrics, Pediatric Genetics Unit, Hacettepe University Medical Faculty, Ankara, Turkey

    Yasemin Alanay

  5. Nutrition and Metabolism Unit, Queen Fabiola Children's University Hospital, Bruxelles, Belgium

    Corinne De Laet & Sylvie Tenoutasse

  6. Institute of Human Genetics, University Hospital Jena, Friedrich-Schiller-University, Jena, Germany

    Christian A Hübner

  7. Clinical Genetics Unit, Children's Hospital Altona, Hamburg, Germany

    Peter Meinecke

  8. Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan.,

    Gen Nishimura

  9. Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.,

    Mari Matsuo & Yoshiko Hirano

  10. Clinical Genetics Division and the Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil

    Andrea Kiss & Rafael Fabiano Machado Rosa

  11. Division of Neonatology, Mount Sinai Hospital, University of Toronto, Toronto, Canada

    Sharon L Unger

  12. Department of Pediatric Hematology-Oncology, Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Raffaele Renella

  13. Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Raffaele Renella, Luisa Bonafé & Andrea Superti-Furga

  14. Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Sheila Unger

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  1. Ekkehart Lausch
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Contributions

E.L. and A.S.-F. conceived and initiated the project and E.L. designed functional studies. B.Z., A.S.-F. and E.L. secured financial support. Y.A., C.D.L., C.A.H., P.M., G.N., M.M., Y.H., S. Tenoutasse, A.K., R.F.M.R., S.L.U., R.R., L.B., J.S., B.Z., E.L. and A.S.-F. identified cases of SPENCD, provided clinical information and collected biologic materials. S.U., R.R., J.S., E.L. and A.S.-F. assessed the clinical and radiographic data for inclusion in the study. A.S.-F., E.L. and A.J. performed linkage and mutation analysis. E.L. performed biochemical analyses and statistical evaluation. E.L., M.B. and S. Trojandt performed the expression studies as well as the functional and immunological studies with dendritic cells. B.Z., S.U. and R.R. discussed the ongoing experiments with E.L. and A.S.-F. Finally, E.L., S.U., B.Z. and A.S.-F. wrote the manuscript.

Corresponding author

Correspondence to Andrea Superti-Furga.

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Lausch, E., Janecke, A., Bros, M. et al. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet 43, 132–137 (2011). https://doi.org/10.1038/ng.749

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