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.