CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome

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Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases1. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor'2 and 'superficial zone protein'3, contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.

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Figure 1: Clinical features of CACP.
Figure 2: Schematic of the CACP proteoglycan and the putative effects of each mutation.
Figure 3: Expression of CACP mRNA in bovine and human tissues.

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We thank the families for participating and S. Gregory, B. Lamb, E. Eichler and members of their labs, J. Ivanovich, K. Gustashaw, J. Preston, C. Williams, H. Kuivaniemi, G. Tromp, A. Superti-Furga, B. Athreya and I. Simsek for sharing their clinical and scientific expertise. This work was supported by a Biomedical Research Grant from the Arthritis Foundation and NIH grant AR43827 (both to M.L.W.).

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Correspondence to Jeffrey M. Trent or Matthew L. Warman.

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