title: Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity.
abstract: 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.
authors.affiliation: Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, University of Freiburg, Freiburg, Germany.
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Andreas
authors.initials: A
authors.lastname: Janecke
authors.forename: Matthias
authors.initials: M
authors.lastname: Bros
authors.forename: Stefanie
authors.initials: S
authors.lastname: Trojandt
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Corinne
authors.initials: C
authors.lastname: De Laet
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Meinecke
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Mari
authors.initials: M
authors.lastname: Matsuo
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Hirano
authors.forename: Sylvie
authors.initials: S
authors.lastname: Tenoutasse
authors.forename: Andrea
authors.initials: A
authors.lastname: Kiss
authors.forename: Rafael Fabiano Machado
authors.initials: RF
authors.lastname: Rosa
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Unger
authors.forename: Raffaele
authors.initials: R
authors.lastname: Renella
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Jürgen
authors.initials: J
authors.lastname: Spranger
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D000135:Acid Phosphatase / Q000172:deficiency* / Q000235:genetics*; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics; D015551:Autoimmunity; D001848:Bone Diseases, Developmental / Q000378:metabolism*; D001842:Bone and Bones / Q000000981:diagnostic imaging; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000737:chemistry*; D002648:Child; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000201:enzymology / Q000235:genetics; D053495:Osteopontin / Q000378:metabolism; D010766:Phosphorylation; D011859:Radiography; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D053495:Osteopontin; C000605510:ACP5 protein, human; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium