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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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.
The authors declare no competing financial interests.
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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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