Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity

Nat Genet. 2011 Feb;43(2):132-7. doi: 10.1038/ng.749. Epub 2011 Jan 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / deficiency*
  • Acid Phosphatase / genetics*
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / genetics
  • Autoimmunity*
  • Bone Diseases, Developmental / metabolism*
  • Bone and Bones / diagnostic imaging
  • Brain / metabolism*
  • Calcium / chemistry*
  • Child
  • Genetic Predisposition to Disease*
  • Homozygote
  • Humans
  • Isoenzymes / deficiency*
  • Isoenzymes / genetics*
  • Male
  • Mutation
  • Osteochondrodysplasias / enzymology
  • Osteochondrodysplasias / genetics
  • Osteopontin / metabolism
  • Phosphorylation
  • Radiography
  • Tartrate-Resistant Acid Phosphatase

Substances

  • Isoenzymes
  • Osteopontin
  • ACP5 protein, human
  • Acid Phosphatase
  • Tartrate-Resistant Acid Phosphatase
  • Calcium

Supplementary concepts

  • Spondyloenchondrodysplasia