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

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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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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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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.

Correspondence to Yanick J Crow.

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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) doi:10.1038/ng.748

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