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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schorr, S., Legum, C. & Ochshorn, M. Spondyloenchondrodysplasia - enchondromatosis with severe platyspondyly in 2 brothers. Radiology 118, 133–139 (1976).
Renella, R. et al. Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: Clinical and radiographic delineation of a pleiotropic disorder. Am. J. Med. Genet. A. 140A, 541–550 (2006).
Navarro, V. et al. Two further cases of spondyloenchondrodysplasia (SPENCD) with immune dysregulation. Am. J. Med. Genet. A. 146A, 2810–2815 (2008).
Tan, E.M. et al. The 1982 revised criteria for the classification of Systemic Lupus Erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).
Raymond, A.A., Zariah, A.A., Samad, S.A., Chin, C.N. & Kong, N.C. Brain calcification in patients with cerebral lupus. Lupus 5, 123–128 (1996).
Hayman, A.R. et al. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development 122, 3151–3162 (1996).
Bune, A.J., Hayman, A.R., Evans, M.J. & Cox, T.M. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disordered macrophage inflammatory responses and reduced clearance of the pathogen, Staphylococcus aureus. Immunology 102, 103–113 (2001).
Crow, M.K. Type I interferon in systemic lupus erythematosus. Curr. Top. Microbiol. Immunol. 316, 359–386 (2007).
Crow, Y.J. & Livingston, J.H. Aicardi-goutieres syndrome: an important Mendelian mimic of congenital infection. Dev. Med. Child Neurol. 50, 410–416 (2008).
Baechler, E.C. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl. Acad. Sci. USA 100, 2610–2615 (2003).
Hayman, A.R., Macary, P., Lehner, P.J. & Cox, T.M. Tartrate-resistant acid phosphatase (Acp 5): identification in diverse human tissues and dendritic cells. J. Histochem. Cytochem. 49, 675–684 (2001).
Muhonen, P. et al. Sequence and TLR9 independent increase of TRACP expression by antisense DNA and siRNA molecules. Biochem. Biophys. Res. Commun. 359, 889–895 (2007).
Suter, A. et al. Overlapping functions of lysosomal acid phosphatase (LAP) and tartrate-resistant acid phosphatase (Acp5) revealed by doubly deficient mice. Development 128, 4899–4910 (2001).
Kariuki, S.N. et al. Age- and gender-specific modulation of serum osteopontin and interferon-alpha by osteopontin genotype in systemic lupus erythematosus. Genes Immun. 10, 487–494 (2009).
Shinohara, M.L. et al. Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat. Immunol. 7, 498–506 (2006).
Weber, G.F. et al. Phosphorylation-dependent interaction of osteopontin with its receptors regulates macrophage migration and activation. J. Leukoc. Biol. 72, 752–761 (2002).
Botto, M. et al. Complement in human diseases: lessons from complement deficiencies. Mol. Immunol. 46, 2774–2783 (2009).
Lee-Kirsch, M.A. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39, 1065–1067 (2007).
Stetson, D.B., Ko, J.S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).
Lood, C. et al. C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum. 60, 3081–3090 (2009).
Santer, D.M. et al. C1q deficiency leads to the defective suppression of IFN-α in response to nucleoprotein containing immune complexes. J. Immunol. 185, 4738–4749 (2010).
Sträter, N. et al. Crystal structures of recombinant human purple Acid phosphatase with and without an inhibitory conformation of the repression loop. J. Mol. Biol. 351, 233–246 (2005).
Campos-Xavier, A.B. et al. Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia. Am. J. Hum. Genet. 84, 760–770 (2009).
Chao, T.Y. et al. Development of immunoassays for serum tartrate-resistant acid phosphatase isofrom 5a. Clin. Chim. Acta 359, 132–140 (2005).
Janckila, A.J., Neustadt, D.H. & Yam, L.T. Significance of serum TRAP in rheumatoid arthritis. J. Bone Miner. Res. 23, 1287–1295 (2008).
Ankel, H., Westra, D.F., Welling-Wester, S. & Lebon, P. Induction of interferon-alpha by glycoprotein D of herpes simplex virus: a possible role of chemokine receptors. Virology 251, 317–326 (1998).
Jabs, W.J., Henning, C., Zawatzky, R. & Kirchner, H. Failure to detect antiviral activity in serum and plasma of healthy individuals displaying high activity in ELISA for IFN-alpha and IFN-beta. J. Interferon Cytokine Res. 19, 463–469 (1999).
Dubos, F. et al. Interferon alpha production in the serum of very young infants after viral infections. Med. Mal. Infect. 34, 561–565 (2004).
Storey, J.D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).
Word, J.M., Lovell, S.C., Richardson, J.S. & Richardson, D.C. Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J. Mol. Biol. 285, 1735–1747 (1999).
Word, J.M. et al. Visualizing and quantifying molecular goodness-of-fit: small-probe contact dots with explicit hydrogen atoms. J. Mol. Biol. 285, 1711–1733 (1999).
Chen, V.B., Davis, I.W. & Richardson, D.C. KiNG (Kinemage, Next Generation): a versatile interactive molecular and scientific visualization program. Protein Sci. 18, 2403–2409 (2009).
Lovell, S.C., Word, J.M., Richardson, J.S. & Richardson, D.C. The penultimate rotamer library. Proteins 40, 389–408 (2000).
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.
The authors declare no competing financial interests.
About this article
Cite this article
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) doi:10.1038/ng.748
The first comprehensive description of the expression profile of genes involved in differential body growth and the immune system of the Jeju Native Pig and miniature pig
Amino Acids (2019)
The Journal of Immunology (2019)
Autoimmunity Reviews (2019)
Comparison of RT-qPCR and Nanostring in the measurement of blood interferon response for the diagnosis of type I interferonopathies