Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, University of Freiburg, Freiburg, Germany.
Nat Genet. 2011 Feb;43(2):132-7. doi: 10.1038/ng.749. Epub 2011 Jan 9.
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.
脊椎和干骺端发育不良、痉挛伴脑钙化、以及对自身免疫性疾病的强烈易感性是遗传性脊椎骨骺发育不良的特征。我们将五个近亲家庭的基因定位到 19p13 染色体上，并在 14 名受影响的个体中发现了 ACP5 的突变，该基因编码抗酒石酸酸性磷酸酶（TRAP），并表明这些突变使受影响个体的血清和细胞中的酶功能丧失。磷酸化骨桥蛋白是一种参与骨吸收和免疫调节的蛋白质，在 TRAP 缺乏个体的血清、尿液和细胞培养物中积累。源自病例的树突状细胞表现出改变的细胞因子谱，并且在混合淋巴细胞反应中比匹配的对照细胞更有效地刺激同种异体 T 细胞增殖。这些发现为骨桥蛋白及其在常见自身免疫性疾病发病机制中的 TRAP 调节作用提供了新的认识。
