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Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature

Nature Genetics volume 43, pages 127–131 (2011)Cite this article

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Abstract

We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log10 odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.

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Figure 1: Bone, brain and skin involvement in cases with mutations in ACP5.
Figure 2: Summary of mutation data.
Figure 3: Levels of TRAP protein and interferon alpha activity in cases with mutations in ACP5.
Figure 4: Computational analysis of missense mutations in the context of protein structure.
Figure 5: Gene expression analysis in cases with TRAP deficiency.

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Acknowledgements

We would like to thank the families for their cooperation in the research presented here; B. Eguia, AP-HP, Department of Dermatology and Allergy, Hôpital Tenon, Paris, France for providing medical images; B. Smith for technical support; and D. Bonthron for insightful comments on the manuscript. We wish to acknowledge L. Wardleworth and A. Hayes from the Microarray Facility, Faculty of Life Sciences, University of Manchester, Manchester, UK. T.A.B. is supported as a Wellcome Trust Clinical Fellow. Y.J.C., J.U. and S.D. acknowledge the Manchester National Institute for Health Research Biomedical Research Centre. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 241779.

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Authors and Affiliations

  1. Manchester Academic Heath Science Centre, University of Manchester, Genetic Medicine, Manchester, UK

    Tracy A Briggs, Gillian I Rice, Sarah Daly, Jill Urquhart, Hannah Gornall, Graeme C M Black, Emma Hilton, Marcin Szynkiewicz & Yanick J Crow

  2. Department of Pediatric Immunology, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital, Hematology and Rheumatology, Paris, France

    Brigitte Bader-Meunier

  3. Department of Pediatrics, J.J.M. Medical College, Davangere, India

    Kannan Baskar, Shankar Baskar & Muralidhar L Kulkarni

  4. Pediatric Nephrology Department, AP-HP, Robert Debré Hospital, Paris, France

    Veronique Baudouin

  5. University of Liverpool, Institute of Child Health, Liverpool, UK

    Michael W Beresford

  6. University of Manchester, Faculty of Life Sciences, Manchester, UK

    Rebecca J Dearman, Emily S Foster, Simon C Lovell & Leo A H Zeef

  7. Department of Paediatrics, University of Leuven, Leuven, Belgium

    Francis de Zegher & Carine Wouters

  8. Department of Dermatology and Allergy, Hôpital Tenon, Paris, France

    Camille Francès

  9. Department of Clinical Veterinary Science, University of Bristol, Bristol, UK

    Alison R Hayman

  10. AP-HP Cochin, Service de Rheumatology A, Paris, France

    Chantal Job-Deslandre

  11. Necker Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM) U781, Paris, France

    Martine Le Merrer

  12. INSERM U986, Paris, France

    Agnes Linglart

  13. Department of Radiology, Innsbruck Medical University, Innsbruck, Austria

    Kathrin Maurer

  14. Department of Immunochemistry, AP-HP, Paris, France

    Lucile Musset

  15. AP-HP, Epilepsy Unit, Paris, France

    Vincent Navarro

  16. INSERM-U980 Necker Faculty, Laboratory of Human Genetics of Infectious Diseases, Paris, France

    Capucine Picard, Anne Puel & Jean-Laurent Casanova

  17. Necker faculty, Paris Descartes University, Paris, France

    Capucine Picard, Anne Puel, Frederic Rieux-Laucat & Jean-Laurent Casanova

  18. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Capucine Picard

  19. Department of Pediatrics IV, Innsbruck Medical University, Neonatology, Neuropediatrics and Inherited Metabolic Disorders, Innsbruck, Austria

    Frederic Rieux-Laucat

  20. Paterson Institute for Cancer Research, University of Manchester, Clinical and Experimental Pharmacology Group, Manchester, UK

    Chaim M Roifman

  21. Department of Medicine, University of Washington, Seattle, Washington, USA

    Sabine Scholl-Bürgi

  22. Department of Immunology, Seattle, Washington, USA

    Nigel Smith

  23. The Rockefeller University, Laboratory of Human Genetics of Infectious Diseases, New York, New York, USA

    Alice Wiedeman & Keith B Elkon

  24. Department of Immunology, University of Washington, Seattle, Washington, USA

    Alice Wiedeman & Keith B Elkon

  25. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, Laboratory of Human Genetics of Infectious Diseases, New York, New York, USA

    Jean-Laurent Casanova

  26. Robley Rex Department of Veterans Affairs Medical Center, Special Hematology Laboratory, Louisville, Kentucky, USA

    Anthony Janckila

  27. Université Paris Descartes, Service Virologie, Paris, France

    Pierre Lebon

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  1. Tracy A Briggs
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Contributions

S.D., J.U. and T.A.B. performed SNP genotyping. T.A.B. performed sequencing with contributions from S.D., H.G., G.I.R. and M.S. QMPSF analysis was undertaken by J.U. and M.S. Interferon assays were conducted by P.L. L.A.H.Z. performed microarray analysis. RT-PCR and qPCR was conducted by G.I.R., T.A.B., H.G., E.H. and E.S.F. Protein assays were preformed by A.J. for TRAP and by N.S. for OPN. ACP5 expression in different human cell types was assessed by K.B.E. and A.W. Lymphocyte subset analysis was conducted by C.P., A.P. and F.R.-L. Bioinformatics analysis was conducted by S.C.L. All other coauthors identified subjects with SPENCD and performed related clinical and laboratory studies (B.B.-M., K.B., S.B., V.B., M.W.B., F.d.Z., C.F., C.J.-D., M.L.K., M.L.M., A.L., K.M., L.M., V.N., C.M.R., S.S.-B. and C.W.). G.I.R., J.-L.C., A.R.H., R.J.D. and G.C.M.B. provided critical input into project development and manuscript preparation. Y.J.C. designed and supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Yanick J Crow.

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The authors declare no competing financial interests.

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Briggs, T., Rice, G., Daly, S. et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet 43, 127–131 (2011). https://doi.org/10.1038/ng.748

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