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

We studied ten individuals from eight families showing features consistent with the immuno-osseus dysplasia spondyloenchondrodysplasia (SPENCD). Of particular note was the diverse spectrum of autoimmune phenotypes observed in these patients, including systemic lupus erythematosus (SLE), Sjögren's syndrome, haemolytic 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 lod score of 3.6. Sequencing of the ACP5 gene, encoding tartrate resistant acid phosphatase (TRAP), identified biallelic mutations in each of the patients studied, and in vivo testing confirmed a loss of expressed protein. All eight patients assayed demonstrated elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognised link between TRAP activity and interferon metabolism, and highlight the importance of type I interferon in the genesis of autoimmunity.