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Judith Vmg Bovée - One of the best experts on this subject based on the ideXlab platform.
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The role of metabolic enzymes in mesenchymal tumors and tumor syndromes: genetics, pathology, and molecular mechanisms
Laboratory Investigation, 2018Co-Authors: Inga-marie Schaefer, Jason L. Hornick, Judith Vmg BovéeAbstract:The discovery of mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) has expanded our understanding not only of altered metabolic pathways but also epigenetic dysregulation in cancer. IDH1/2 mutations occur in enchondromas and chondrosarcomas in patients with the non-hereditary enchondromatosis syndromes Ollier Disease and Maffucci syndrome and in sporadic tumors. IDH1/2 mutations result in excess production of the oncometabolite ( d )-2-hydroxyglutarate. In contrast, SDH and FH act as tumor suppressors and genomic inactivation results in succinate and fumarate accumulation, respectively. SDH deficiency may result from germline SDHA , SDHB , SDHC , or SDHD mutations and is found in autosomal-dominant familial paraganglioma/pheochromocytoma and Carney-Stratakis syndrome, describing the combination of paraganglioma and gastrointestinal stromal tumor (GIST). In contrast, patients with the non-hereditary Carney triad, including paraganglioma, GIST, and pulmonary chondroma, usually lack germline SDH mutations and instead show epigenetic SDH complex inactivation through SDHC promoter methylation. Inactivating FH germline mutations are found in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome comprising benign cutaneous/uterine leiomyomas and renal cell carcinoma. Mutant IDH, SDH, and FH share common inhibition of α-ketoglutarate-dependent oxygenases such as the TET family of 5-methylcytosine hydroxylases preventing DNA demethylation, and Jumonji domain histone demethylases increasing histone methylation, which together inhibit cell differentiation. Ongoing studies aim to better characterize these complex alterations in cancer, the different clinical phenotypes, and variable penetrance of inherited and sporadic cancer predisposition syndromes. A better understanding of the roles of metabolic enzymes in cancer may foster the development of therapies that specifically target functional alterations in tumor cells in the future. Here, the physiologic functions of these metabolic enzymes, the mutational spectrum, and associated functional alterations will be discussed, with a focus on mesenchymal tumor predisposition syndromes.
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incidence predictive factors and prognosis of chondrosarcoma in patients with Ollier Disease and maffucci syndrome an international multicenter study of 161 patients
Oncologist, 2011Co-Authors: Suzan Hm Verdegaal, Twinkal C Pansuriya, Judith Vmg Bovée, Robert J Grimer, Paul C Jutte, David Biau, I C M Van Der Geest, Harzem Ozger, Mikel San Julian, Andreas LeithnerAbstract:Background. Enchondromatosis is characterized by the presence of multiple benign cartilage lesions in bone. While Ollier Disease is typified by multiple enchondromas, in Maffucci syndrome these are associated with hemangiomas. Studies evaluating the predictive value of clinical symptoms for development of secondary chondrosarcoma and prognosis are lacking. This multi-institute study evaluates the clinical characteristics of patients, to get better insight on behavior and prognosis of these Diseases. Method.Aretrospectivestudywasconductedusingclinical dataof144Ollierand17Maffuccipatientsfrom13European centers and one national databank supplied by members of the European Musculoskeletal Oncology Society. Results. Patients had multiple enchondromas in the hands and feet only (group I, 18%), in long bones including scapula and pelvis only (group II, 39%), and in both small and long/flat bones (group III, 43%), respectively. The overall incidence of chondrosarcoma thus far is 40%. In group I, only 4 patients (15%) developed chondrosarcoma, in contrast to 27 patients (43%) in group II and 26 patients (46%) in group III, respectively. The risk of developing chondrosarcoma is increased when enchondromas are located in the pelvis (odds ratio, 3.8; p 0.00l). Conclusions. Overall incidence of development of chondrosarcoma is 40%, but may, due to age-dependency, increase when considered as a lifelong risk. Patients with
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Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier Disease or maffucci syndrome
PLOS Genetics, 2011Co-Authors: Margot E. Bowen, Judith Vmg Bovée, Eric D. Boyden, Ingrid A. Holm, Belinda Campos-xavier, Luisa Bonafé, Andrea Superti-furga, Shiro Ikegawa, Valérie Cormier-daire, Twinkal C PansuriyaAbstract:Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier Disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a ‘‘second hit,’’ that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious Disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier Disease or Maffucci syndrome.
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Genome-wide analysis of Ollier Disease: Is it all in the genes?
Orphanet Journal of Rare Diseases, 2011Co-Authors: Twinkal C Pansuriya, Jan Oosting, Tibor Krenács, Antonie Hm Taminiau, Suzan Hm Verdegaal, Luca Sangiorgi, Raf Sciot, Pancras Cw Hogendoorn, Karoly Szuhai, Judith Vmg BovéeAbstract:Background Ollier Disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier Disease is unknown. Methods We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina BeadArray v3.0 for 7 ECs of 6 patients. Results Non-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identified loss as well as down regulation of POU5F1 and gain as well as up regulation of NIPBL . None of these candidate regions were affected in more than two Ollier patients suggesting these changes to be random secondary events in EC development. An increased number of genetic alterations and LOH were found in Ollier CS which mainly involves chromosomes 9p, 6q, 5q and 3p. Conclusions We present the first genome-wide analysis of the largest international series of Ollier ECs and CS reported so far and demonstrate that copy number alterations and LOH are rare and non-recurrent in Ollier ECs while secondary CS are genetically unstable. One could predict that instead small deletions, point mutations or epigenetic mechanisms play a role in the origin of ECs of Ollier Disease.
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3 o 10 incidence predictive factors and prognosis of central chondrosarcoma in patients with Ollier Disease and maffucci syndrome report of 133 patients
Journal of Bone and Joint Surgery-british Volume, 2010Co-Authors: Suzan Hm Verdegaal, Twinkal C Pansuriya, Judith Vmg Bovée, Robert J Grimer, B Toker, Paul C Jutte, San M Julian, David Biau, I C M Van Der Geest, Andreas LeithnerAbstract:Enchondromatosis is a non-hereditary Disease, characterised by the presence of multiple enchondromas. While Ollier Disease is typified by multiple enchondromas, in Maffucci Syndrome they are combined with haemangioma. Due to the rarity of these Diseases, systematic studies on clinical behaviour providing information how to treat patients are lacking. This study intends to answer the following questions: What are predictive factors for developing chondrosarcoma? When is extensive surgery necessary? How often patients die due to dedifferentiation or metastasis? Twelve institutes in eight countries participated in this descriptive retrospective EMSOS-study. 118 Patients with Ollier Disease and 15 patients with Maffucci Syndrome were included. Unilateral localization of Disease was found in 60% of Ollier patients and 40% of patients with Maffucci Syndrome. One of the predictive factors for developing chondrosarcoma is the location of the enchondromas; the risk increases especially when enchondromas are located in the scapula (33%), humerus (18%), pelvis (26%) or femur (15%). For the phalanges, this risk is 14% in the hand and 16% in the feet. The decision whether or not to perform extensive surgery is difficult, especially in patients who suffer multiple chondrosarcomas. Malignant transformation was found in fourty-four patients with Ollier Disease (37%) and eight patients with Maffucci Syndrome (53%). Multiple synchronous or metachronous chondrosarcomas were found in 15 patients. Nine patients died (range 21–54 yrs). Seven of them died Disease related due to pulmonary metastasis (2 humerus, 2 pelvis, 3 femur). Two patients died from glioma of the brain. In conclusion, one important predictive factor for developing chondrosarcoma is the location of the enchondromas; interestingly, only patients with chondrosarcoma outside the small bones died of their Disease. In this series, no dedifferentiation of chondrosarcoma was seen. A first design flow-chart how to approach chondrosarcoma in patients with Ollier Disease and Maffucci Syndrome is in preparation.
Twinkal C Pansuriya - One of the best experts on this subject based on the ideXlab platform.
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somatic mosaic idh1 and idh2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier Disease and maffucci syndrome
Nature Genetics, 2011Co-Authors: Twinkal C Pansuriya, Jan Oosting, Ronald Van Eijk, Pio Dadamo, Maayke A J H Van Ruler, Marieke L Kuijjer, Annemarie Cletonjansen, Jolieke G Van Oosterwijk, Sofie L J Verbeke, Danielle MeijerAbstract:Ollier Disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier Disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier Disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.
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incidence predictive factors and prognosis of chondrosarcoma in patients with Ollier Disease and maffucci syndrome an international multicenter study of 161 patients
Oncologist, 2011Co-Authors: Suzan Hm Verdegaal, Twinkal C Pansuriya, Judith Vmg Bovée, Robert J Grimer, Paul C Jutte, David Biau, I C M Van Der Geest, Harzem Ozger, Mikel San Julian, Andreas LeithnerAbstract:Background. Enchondromatosis is characterized by the presence of multiple benign cartilage lesions in bone. While Ollier Disease is typified by multiple enchondromas, in Maffucci syndrome these are associated with hemangiomas. Studies evaluating the predictive value of clinical symptoms for development of secondary chondrosarcoma and prognosis are lacking. This multi-institute study evaluates the clinical characteristics of patients, to get better insight on behavior and prognosis of these Diseases. Method.Aretrospectivestudywasconductedusingclinical dataof144Ollierand17Maffuccipatientsfrom13European centers and one national databank supplied by members of the European Musculoskeletal Oncology Society. Results. Patients had multiple enchondromas in the hands and feet only (group I, 18%), in long bones including scapula and pelvis only (group II, 39%), and in both small and long/flat bones (group III, 43%), respectively. The overall incidence of chondrosarcoma thus far is 40%. In group I, only 4 patients (15%) developed chondrosarcoma, in contrast to 27 patients (43%) in group II and 26 patients (46%) in group III, respectively. The risk of developing chondrosarcoma is increased when enchondromas are located in the pelvis (odds ratio, 3.8; p 0.00l). Conclusions. Overall incidence of development of chondrosarcoma is 40%, but may, due to age-dependency, increase when considered as a lifelong risk. Patients with
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Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier Disease or maffucci syndrome
PLOS Genetics, 2011Co-Authors: Margot E. Bowen, Judith Vmg Bovée, Eric D. Boyden, Ingrid A. Holm, Belinda Campos-xavier, Luisa Bonafé, Andrea Superti-furga, Shiro Ikegawa, Valérie Cormier-daire, Twinkal C PansuriyaAbstract:Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier Disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a ‘‘second hit,’’ that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious Disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier Disease or Maffucci syndrome.
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Genome-wide analysis of Ollier Disease: Is it all in the genes?
Orphanet Journal of Rare Diseases, 2011Co-Authors: Twinkal C Pansuriya, Jan Oosting, Tibor Krenács, Antonie Hm Taminiau, Suzan Hm Verdegaal, Luca Sangiorgi, Raf Sciot, Pancras Cw Hogendoorn, Karoly Szuhai, Judith Vmg BovéeAbstract:Background Ollier Disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier Disease is unknown. Methods We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina BeadArray v3.0 for 7 ECs of 6 patients. Results Non-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identified loss as well as down regulation of POU5F1 and gain as well as up regulation of NIPBL . None of these candidate regions were affected in more than two Ollier patients suggesting these changes to be random secondary events in EC development. An increased number of genetic alterations and LOH were found in Ollier CS which mainly involves chromosomes 9p, 6q, 5q and 3p. Conclusions We present the first genome-wide analysis of the largest international series of Ollier ECs and CS reported so far and demonstrate that copy number alterations and LOH are rare and non-recurrent in Ollier ECs while secondary CS are genetically unstable. One could predict that instead small deletions, point mutations or epigenetic mechanisms play a role in the origin of ECs of Ollier Disease.
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3 o 10 incidence predictive factors and prognosis of central chondrosarcoma in patients with Ollier Disease and maffucci syndrome report of 133 patients
Journal of Bone and Joint Surgery-british Volume, 2010Co-Authors: Suzan Hm Verdegaal, Twinkal C Pansuriya, Judith Vmg Bovée, Robert J Grimer, B Toker, Paul C Jutte, San M Julian, David Biau, I C M Van Der Geest, Andreas LeithnerAbstract:Enchondromatosis is a non-hereditary Disease, characterised by the presence of multiple enchondromas. While Ollier Disease is typified by multiple enchondromas, in Maffucci Syndrome they are combined with haemangioma. Due to the rarity of these Diseases, systematic studies on clinical behaviour providing information how to treat patients are lacking. This study intends to answer the following questions: What are predictive factors for developing chondrosarcoma? When is extensive surgery necessary? How often patients die due to dedifferentiation or metastasis? Twelve institutes in eight countries participated in this descriptive retrospective EMSOS-study. 118 Patients with Ollier Disease and 15 patients with Maffucci Syndrome were included. Unilateral localization of Disease was found in 60% of Ollier patients and 40% of patients with Maffucci Syndrome. One of the predictive factors for developing chondrosarcoma is the location of the enchondromas; the risk increases especially when enchondromas are located in the scapula (33%), humerus (18%), pelvis (26%) or femur (15%). For the phalanges, this risk is 14% in the hand and 16% in the feet. The decision whether or not to perform extensive surgery is difficult, especially in patients who suffer multiple chondrosarcomas. Malignant transformation was found in fourty-four patients with Ollier Disease (37%) and eight patients with Maffucci Syndrome (53%). Multiple synchronous or metachronous chondrosarcomas were found in 15 patients. Nine patients died (range 21–54 yrs). Seven of them died Disease related due to pulmonary metastasis (2 humerus, 2 pelvis, 3 femur). Two patients died from glioma of the brain. In conclusion, one important predictive factor for developing chondrosarcoma is the location of the enchondromas; interestingly, only patients with chondrosarcoma outside the small bones died of their Disease. In this series, no dedifferentiation of chondrosarcoma was seen. A first design flow-chart how to approach chondrosarcoma in patients with Ollier Disease and Maffucci Syndrome is in preparation.
Christian Manuel Claus Jacobi - One of the best experts on this subject based on the ideXlab platform.
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enchondroma of the nasal septum due to Ollier Disease a case report and review of the literature
Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 2015Co-Authors: Christian Manuel Claus Jacobi, Egodage Samitha Hiranya, David Holzmann, S Kollias, Michael B SoykaAbstract:Background Morbus Ollier is characterized by the presence of multiple enchondromas (ie, benign intraosseous cartilaginous lesions). Although their manifestation in the limb bones is well described, only a few cases with ear, nose, and throat (ENT) involvement, primarily arising from the skull, have been reported. The malignant transformation toward slowly growing low-grade chondrosarcomas is the most severe form of progression. Methods We report a unique case of a 54-year-old patient with Ollier Disease with an extensive nasal enchondroma apparently eroding the middle nasal concha and expanding to the lateral nasal wall that raised suspicion of malignant transformation. Results Radiological and histological features of enchondromas can be controversial and seem to have limited sensitivity to exclude low-grade malignancy. The clinical symptoms play a decisive role in differentiation between enchondromas and low-grade chondrosarcomas. Conclusion Surgery remains the only effective solution in removing an enchondroma and preventing the tendency toward malignant transformation. © 2014 Wiley Periodicals, Inc. Head Neck 37: E30–E33, 2015
Ba D Nguyen - One of the best experts on this subject based on the ideXlab platform.
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Ollier Disease with digital enchondromatosis anatomic and functional imaging
Clinical Nuclear Medicine, 2014Co-Authors: Ba D NguyenAbstract:Ollier Disease is a rare skeletal disorder characterized by multiple enchondromas at metaphyseal regions of the bones. The Disease is nonhereditary and usually the result of postzygote mutations during development. We present the features of digital enchondromatosis on bone scintigraphy, PET/CT, radiographs, and MRI in a patient, with a childhood diagnosis of Ollier Disease.
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scintigraphic functional and conventional cross sectional imaging of Ollier Disease
The Journal of Nuclear Medicine, 2013Co-Authors: Ba D NguyenAbstract:1256 Learning Objectives 1. To present the bone scintigraphic and PET/CT features of Ollier Disease with corresponding radiographic and cross-sectional imaging. 2. To highlight the imaging patterns of sarcomatous transformation of enchondromatosis. Originally reported by Ollier in 1899, this non-hereditary osseous malformation consists of multiple enchondromas involving frequently the pelvis and lower extremities. The enchondromatosis may be bilateral with one side predominance, monomelic or hemi-skeletal. Diagnosis is made early during childhood in patients presenting with asymmetric limb length, extremity deformities and masses from enchondromas. The lifetime risk of chondrosarcoma in Ollier Disease is up to 30%. Malignant transformation of enchondroma to chondrosarcoma manifests with painful tumor enlargement. The authors present two cases of Ollier Disease with multi-modality imaging, including technetium-99m MDP bone scintigraphy and F-18 FDG PET/CT, of enchondromatosis and its chondrosarcomatous degeneration.
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Ollier Disease with synchronous multicentric chondrosarcomas scintigraphic and radiologic demonstration
Clinical Nuclear Medicine, 2004Co-Authors: Ba D NguyenAbstract:Ollier Disease is a nonhereditary dyschondroplasia usually diagnosed during early childhood. It is characterized by the presence of multiple enchondromas affecting predominantly limbs unilaterally or bilaterally. As this dysplasia progresses, there is an increased risk of malignant degeneration into
Caroline Silve - One of the best experts on this subject based on the ideXlab platform.
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pthr1 mutations associated with Ollier Disease result in receptor loss of function
Human Molecular Genetics, 2008Co-Authors: Alain Couvineau, Vinciane Wouters, Guylene Bertrand, Christiane Rouyer, Benedicte Gerard, Laurence M Boon, Bernard Grandchamp, Miikka Vikkula, Caroline SilveAbstract: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.
