PTHR1 mutations associated with Ollier disease result in receptor loss of function

Hum Mol Genet. 2008 Sep 15;17(18):2766-75. doi: 10.1093/hmg/ddn176. Epub 2008 Jun 17.


PTHR1-signaling pathway is critical for the regulation of endochondral ossification. Thus, abnormalities in genes belonging to this pathway could potentially participate in the pathogenesis of Ollier disease/Maffucci syndrome, two developmental disorders defined by the presence of multiple enchondromas. In agreement, a functionally deleterious mutation in PTHR1 (p.R150C) was identified in enchondromas from two of six unrelated patients with enchondromatosis. However, neither the p.R150C mutation (26 tumors) nor any other mutation in the PTHR1 gene (11 patients) could be identified in another study. To further define the role of PTHR1-signaling pathway in Ollier disease and Maffucci syndrome, we analyzed the coding sequences of four genes (PTHR1, IHH, PTHrP and GNAS1) in leucocyte and/or tumor DNA from 61 and 23 patients affected with Ollier disease or Maffucci syndrome, respectively. We identified three previously undescribed missense mutations in PTHR1 in patients with Ollier disease at the heterozygous state. Two mutations (p.G121E, p.A122T) were present only in enchondromas, and one (p.R255H) in both enchondroma and leukocyte DNA. Assessment of receptor function demonstrated that these three mutations impair PTHR1 function by reducing either the affinity of the receptor for PTH or the receptor expression at the cell surface. These mutations were not found in DNA from 222 controls. Including our data, PTHR1 functionally deleterious mutations have now been identified in five out 31 enchondromas from Ollier patients. These findings provide further support for the idea that heterozygous mutations in PTHR1 that impair receptor function participate in the pathogenesis of Ollier disease in some patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • CHO Cells
  • COS Cells
  • Child
  • Chlorocebus aethiops
  • Chondroma / genetics
  • Chondroma / metabolism
  • Chondroma / physiopathology
  • Cohort Studies
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Enchondromatosis / genetics*
  • Enchondromatosis / metabolism
  • Enchondromatosis / physiopathology*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense*
  • Parathyroid Hormone / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptor, Parathyroid Hormone, Type 1 / chemistry
  • Receptor, Parathyroid Hormone, Type 1 / genetics*
  • Receptor, Parathyroid Hormone, Type 1 / metabolism*
  • Signal Transduction


  • PTH1R protein, human
  • Parathyroid Hormone
  • Receptor, Parathyroid Hormone, Type 1
  • Cyclic AMP