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

Abstract

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.

Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth

“…We found IPI-926 to be a very effective antitumor agent in primary chondrosarcoma xenografts, regardless of whether treatment was initiated at the time of tumor For most tumors, it remains controversial whether Hh signaling occurs in the tumor cells themselves, stromal cells, or both. Chondrosarcoma is an example of a tumor with ligand-dependent Hh signaling as it expresses high levels of Ihh, and only rarely harbors mutations in pathway-specific genes (11,(26)(27)(28). We utilized species-specific RT-PCR primers to address the controversial issue of whether Hh functions through an autocrine or paracrine mechanism in chondrosarcoma.…”

Diffuse gliomas in an adolescent with multiple enchondromatosis (Ollier’s disease)

“…Consistent with this hypothesis, a functionally deleterious mutation in parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) type 1 receptor (PTHR1)(R150C) was identified in enchondromas in 2 out of 6 unrelated patients with enchondromatosis (16). PTHR1 interacts with the parathyroid hormone and PTHrP and appears to play a local role in the regulation of chondrocyte differentiation and enchondral ossification (17). On the other hand, PTHrP was found to be expressed in astrocytic tumors (18) and to regulate glioma-associated oncogene transcriptional activation (18).…”

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

“…Four other heterozygous PTHR1 point mutations: G121E, A122T, R150C, and R255H, the first three of which also map to the receptor's ECD region and impair receptor function, have been identified in Ollier disease, a development condition defined by the occurrence of multiple enchondromas (Hopyan et al, 2002;Couvineau et al, 2008). A homozygous stop codon mutation (R485-stop) in the PTHR1 that results in a receptor with a truncated C-terminal tail has been identified in a patient with Eiken syndrome, a very rare recessive skeletal dysplasia in which ossification is severely delayed (Duchatelet et al, 2005).…”