Human Molecular Genetics Advance Access originally published online on June 17, 2008
Human Molecular Genetics 2008 17(18):2766-2775; doi:10.1093/hmg/ddn176
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PTHR1 mutations associated with Ollier disease result in receptor loss of function
1 INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3 2 AP-HP, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique, Université Paris 7, UFR Médicale, 75018 Paris, France 3 Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, B-1348 Brussels, Belgium 4 Division of Plastic Surgery, Center for Vascular Anomalies, Cliniques universitaires St Luc, 10-1200 Brussels, Belgium
* To whom correspondence should be addressed. Tel: +33 1 40 48 80 17; Fax: +33 1 40 48 83 40; Email: caroline.silve{at}inserm.fr
Received April 24, 2008; Accepted June 14, 2008
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.
Present address: INSERM U561, Hôpital Saint Vincent de Paul, 84 avenue Denfert Rochereau, 75014 Paris, France.