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3. Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis

Author

Marine Delamare, Amandine Le Roy, Mathilde Pacault, Loïc Schmitt, Céline Garrec, Nada Maaziz, Matti Myllykoski, Antoine Rimbert, Valéna Karaghiannis, Bernard Aral, Mark Catherwood, Fabrice Airaud, Lamisse Mansour-Hendili, David Hoogewijs, Edoardo Peroni, Salam Idriss, Valentine Lesieur, Amandine Caillaud, Karim Si-Tayeb, Caroline Chariau, Anne Gaignerie, Minke Rab, Torsten Haferlach, Manja Meggendorfer, Stéphane Bézieau, Andrea Benetti, Nicole Casadevall, Pierre Hirsch, Christian Rose, Mathieu Wemeau, Frédéric Galacteros, Bruno Cassinat, Beatriz Bellosillo, Celeste Bento, Richard van Wijk, Petro E. Petrides, Maria Luigia Randi, Mary Frances McMullin, Peppi Koivunen, François Girodon, Betty Gardie, and ECYT consortium

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Hereditary erythrocytosis is a rare hematologic disorder characterized by an excess of red blood cell production. Here we describe a European collaborative study involving a collection of 2,160 patients with erythrocytosis sequenced in ten different laboratories. We focused our study on the EGLN1 gene and identified 39 germline missense variants including one gene deletion in 47 probands. EGLN1 encodes the PHD2 prolyl 4-hydroxylase, a major inhibitor of hypoxia-inducible factor. We performed a comprehensive study to evaluate the causal role of the identified PHD2 variants: (i) in silico studies of localization, conservation, and deleterious effects; (ii) analysis of hematologic parameters of carriers identified in the UK Biobank; (iii) functional studies of the protein activity and stability; and (iv) a comprehensive study of PHD2 splicing. Altogether, these studies allowed the classification of 16 pathogenic or likely pathogenic mutants in a total of 48 patients and relatives. The in silico studies extended to the variants described in the literature showed that a minority of PHD2 variants can be classified as pathogenic (36/96), without any differences from the variants of unknown significance regarding the severity of the developed disease (hematologic parameters and complications). Here, we demonstrated the great value of federating laboratories working on such rare disorders in order to implement the criteria required for genetic classification, a strategy that should be extended to all hereditary hematologic diseases.

Published
2023
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4. Comprehensive in silico and functional studies for classification of EPAS1/HIF2A genetic variants identified in patients with erythrocytosis

Author

Valéna Karaghiannis, Darko Maric, Céline Garrec, Nada Maaziz, Alexandre Buffet, Loïc Schmitt, Vincent Antunes, Fabrice Airaud, Bernard Aral, Amandine Le Roy, Sébastien Corbineau, Lamisse Mansour-Hendili, Valentine Lesieur, Antoine Rimbert, Fabien Laporte, Marine Delamare, Minke Rab, Stéphane Bézieau, Bruno Cassinat, Frédéric Galacteros, Anne-Paule Gimenez-Roqueplo, Nelly Burnichon, Holger Cario, Richard van Wijk, Celeste Bento, François Girodon, David Hoogewijs, and Betty Gardie

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Gain-of-function mutations in the EPAS1/HIF2A gene have been identified in patients with hereditary erythrocytosis that can be associated with the development of paraganglioma, pheochromocytoma and somatostatinoma. In the present study, we describe a unique European collection of 41 patients and 28 relatives diagnosed with an erythrocytosis associated with a germline genetic variant in EPAS1. In addition we identified two infants with severe erythrocytosis associated with a mosaic mutation present in less than 2% of the blood, one of whom later developed a paraganglioma. The aim of this study was to determine the causal role of these genetic variants, to establish pathogenicity, and to identify potential candidates eligible for the new hypoxia-inducible factor-2 α (HIF-2α) inhibitor treatment. Pathogenicity was predicted with in silico tools and the impact of 13 HIF-2b variants has been studied by using canonical and real-time reporter luciferase assays. These functional assays consisted of a novel edited vector containing an expanded region of the erythropoietin promoter combined with distal regulatory elements which substantially enhanced the HIF-2α-dependent induction. Altogether, our studies allowed the classification of 11 mutations as pathogenic in 17 patients and 23 relatives. We described four new mutations (D525G, L526F, G527K, A530S) close to the key proline P531, which broadens the spectrum of mutations involved in erythrocytosis. Notably, we identified patients with only erythrocytosis associated with germline mutations A530S and Y532C previously identified at somatic state in tumors, thereby raising the complexity of the genotype/phenotype correlations. Altogether, this study allows accurate clinical follow-up of patients and opens the possibility of benefiting from HIF-2α inhibitor treatment, so far the only targeted treatment in hypoxia-related erythrocytosis disease.

Published
2023
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5. FACS-assisted CRISPR-Cas9 genome editing of human induced pluripotent stem cells

Author

Amandine Caillaud, Antoine Lévêque, Aurélie Thédrez, Aurore Girardeau, Robin Canac, Lise Bray, Manon Baudic, Julien Barc, Nathalie Gaborit, Guillaume Lamirault, Betty Gardie, Salam Idriss, Antoine Rimbert, Cédric Le May, Bertrand Cariou, and Karim Si-Tayeb

Subjects
CRISPR, Flow cytometry/Mass cytometry, Stem cells, Science (General), Q1-390
Abstract

Summary: This manuscript proposes an efficient and reproducible protocol for the generation of genetically modified human induced pluripotent stem cells (hiPSCs) by genome editing using CRISPR-Cas9 technology. Here, we describe the experimental strategy for generating knockout (KO) and knockin (KI) clonal populations of hiPSCs using single-cell sorting by flow cytometry. We efficiently achieved up to 15 kb deletions, molecular tag insertions, and single-nucleotide editing in hiPSCs. We emphasize the efficacy of this approach in terms of cell culture time.For complete details on the use and execution of this protocol, please refer to Canac et al. (2022) and Bray et al. (2022). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Published
2022
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6. Diagnosis of exon 12‐positive polycythemia vera rescued by NGS

Author

Antoine Geay, Bernard Aral, Valentin Bourgeois, Pauline Martin, Fabrice Airaud, Céline Garrec, Stéphane Bézieau, Betty Gardie, and François Girodon

Subjects
erythrocytosis, Exon 12, JAK2, next generation sequencing, polycythemia vera, Medicine, Medicine (General), R5-920
Abstract

Abstract A JAK2V617F‐negative polycythemia associated with low serum epo needs to be tested for an exon 12 JAK2 mutation. When negative, due to potential serious complications in PV, a next generation sequencing is necessary to rule out false negative results.

Published
2020
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7. Low incidence of EPOR mutations in idiopathic erythrocytosis

Author

Mathilde Filser, Bernard Aral, Fabrice Airaud, Aurélie Chauveau, Aisha Bruce, Yann Polfrit, Anne Thiebaut, Martin Gauthier, Cédric Le Maréchal, Eric Lippert, Stéphane Béziau, Céline Garrec, Betty Gardie, and François Girodon

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2020
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9. Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

Author

Sylvie Hermouet, Edith Bigot-Corbel, and Betty Gardie

Subjects
Pathology, RB1-214
Abstract

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in the JAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients with JAK2-mutated MPNs may not be the consequence of JAK2 mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation.

Published
2015
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10. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Author

Charline Ladroue, David Hoogewijs, Sophie Gad, Romain Carcenac, Federica Storti, Michel Barrois, Anne-Paule Gimenez-Roqueplo, Michel Leporrier, Nicole Casadevall, Olivier Hermine, Jean-Jacques Kiladjian, André Baruchel, Fadi Fakhoury, Brigitte Bressac-de Paillerets, Jean Feunteun, Nathalie Mazure, Jacques Pouysségur, Roland H. Wenger, Stéphane Richard, and Betty Gardie

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma.Design and Methods Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively.Results This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category.Conclusions As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.

Published
2012
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11. A study of 36 unrelated cases with pure erythrocytosis revealed three new mutations in the erythropoietin receptor gene

Author

Maha Al-Sheikh, Elodie Mazurier, Betty Gardie, Nicole Casadevall, Frédéric Galactéros, Michel Goossens, Henri Wajcman, Claude Préhu, and Valérie Ugo

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Thirty-six unrelated cases with erythrocytosis of unknown origin were investigated. Exons 5–8 of the erythropoietin receptor gene (EPOR), the von Hippel-Lindau gene, and the prolyl hydroxylase domain protein 2 gene (PHD2) were screened by direct DNA sequencing. The Janus kinase 2 mutation, JAK2 (Val617Phe), was screened by allele specific PCR. In this study, three new mutations of EPOR causing deletions in exon 8 were found: the first led directly to a stop codon [g.5957_5958delTT (p.Phe424X)], the second to a stop codon after one residue [g.5828_5829delCC (p.Pro381GlnfsX1)] and the third to a stop codon following a frameshift sequence of 23 residues [g.5971delC (p.Leu429TrpfsX23)]. One patient had a previously reported EPOR mutation [g.6146A>G (p.Asn487Ser)] and another, a silent one (g.5799G>A). All were heterozygotes. In addition, 2 patients were positive for JAK2 (Val617Phe), and 2 reported elsewhere, were mutated in the PHD2 gene [c.606delG (p.Met202IlefsX71).

Published
2008
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12. Heterozygosity for bisphosphoglycerate mutase deficiency expressing clinically as congenital erythrocytosis: A case series and literature review

Author

Myrthe J. van Dijk, Brigitte A. van Oirschot, Manon C. Stam‐Slob, Esmé Waanders, Bert van der Zwaag, Eduard J. van Beers, Judith J. M. Jans, Peter Willem van der Linden, Jose M. Torregrosa Diaz, Betty Gardie, François Girodon, Rik Schots, Noortje Thielen, Richard van Wijk, Clinical sciences, and Hematology

Subjects
bisphosphoglycerate mutase deficiency, Congenital, Heterozygosity, Internal Medicine, red blood cell mass, Hematology, Erythrocytosis, clinical
Abstract

Erythrocytosis is associated with increased red blood cell mass and can be either congenital or acquired. Congenital secondary causes are rare and include germline variants increasing haemoglobin (Hb)-oxygen affinity (e.g., Hb or bisphosphoglycerate mutase (BPGM) variants) or affecting oxygen-sensing pathway proteins. Here, we describe five adults from three kindreds with erythrocytosis associated with heterozygosity for BPGM variants, including one novel. Functional analyses showed partial BPGM deficiency, reduced 2,3-bisphosphoglycerate levels and/or increased Hb-oxygen affinity. We also review currently known BPGM variants. This study contributes to raising awareness of BPGM variants, and in particular that heterozygosity for BPGM deficiency may already manifest clinically.

Published
2022
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13. Germline JAK2 E846D Substitution as the Cause of Erythrocytosis?

Author

Nada Maaziz, Céline Garrec, Fabrice Airaud, Victor Bobée, Nathalie Contentin, Emilie Cayssials, Antoine Rimbert, Bernard Aral, Stéphane Bézieau, Betty Gardie, and François Girodon

Subjects
Genetics, erythrocytosis, JAK2 mutation, germline mutation, familial erythrocytosis, Genetics (clinical)
Abstract

The discovery in 2005 of the JAK2 V617F gain-of-function mutation in myeloproliferative neoplasms and more particularly in polycythemia vera has deeply changed the diagnostic and therapeutic approaches to polycythemia. More recently, the use of NGS in routine practice has revealed a large number of variants, although it is not always possible to classify them as pathogenic. This is notably the case for the JAK2 E846D variant for which for which questions remain unanswered. In a large French national cohort of 650 patients with well-characterized erythrocytosis, an isolated germline heterozygous JAK2 E846D substitution was observed in only two cases. For one of the patients, a family study could be performed, without segregation of the variant with the erythrocytosis phenotype. On the other hand, based on the large UK Biobank resource cohort including more than half a million UK participants, the JAK2 E846D variant was found in 760 individuals, associated with a moderate increase in hemoglobin and hematocrit values, but with no significant difference to the mean values of the rest of the studied population. Altogether, our data as well as UK Biobank cohort analyses suggest that the occurrence of an absolute polycythemia cannot be attributed to the sole demonstration of an isolated JAK2 E846D variant. However, it must be accompanied by other stimuli or favoring factors in order to generate absolute erythrocytosis.

Published
2023
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15. Supplementary Figures S1-S5 from ITPR1 Protects Renal Cancer Cells against Natural Killer Cells by Inducing Autophagy

Author

Salem Chouaib, Bernard Escudier, Daniel Olive, Jerome Thiery, Laurence Albiges, Florence Orlanducci, Betty Gardie, Sophie Couve, Emmanuel Donnadieu, Sophie Ferlicot, Catherine Richon, Thouraya Ben Safta, Arash Nanbakhsh, Katy Billot, Elodie Viry, Véronique Baud, Marie Boutet, Andrés Tittarelli, Bassam Janji, Meriem Hasmim, Muhammad Zaeem Noman, and Yosra Messai

Abstract

Supplementary Figures S1-S5. Figure S1. Differential susceptibility of 786-0, PRC3, and WT7 cell lines to NK-mediated lysis. Figure S2. Role of ANGPTL4 and ADM in RCC cell susceptibility to NK-mediated lysis. Figure S3. VHL and NK ligand expression in RCC cells. Figure S4. Silencing of HIF-2α and NK ligand expression in 786-0 cells. Figure S5. VHL status, targeting of HIF-2α or silencing of ITPR1 does not regulate autophagy in 786-0 cells.

Published
2023
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16. Supplemental video 2 from ITPR1 Protects Renal Cancer Cells against Natural Killer Cells by Inducing Autophagy

Author

Salem Chouaib, Bernard Escudier, Daniel Olive, Jerome Thiery, Laurence Albiges, Florence Orlanducci, Betty Gardie, Sophie Couve, Emmanuel Donnadieu, Sophie Ferlicot, Catherine Richon, Thouraya Ben Safta, Arash Nanbakhsh, Katy Billot, Elodie Viry, Véronique Baud, Marie Boutet, Andrés Tittarelli, Bassam Janji, Meriem Hasmim, Muhammad Zaeem Noman, and Yosra Messai

Abstract

Supplemental video 2. 786-0 cells described in Figure 3B were recorded by time-lapse video microscopy

Published
2023
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17. Supplemental video 1 from ITPR1 Protects Renal Cancer Cells against Natural Killer Cells by Inducing Autophagy

Author

Salem Chouaib, Bernard Escudier, Daniel Olive, Jerome Thiery, Laurence Albiges, Florence Orlanducci, Betty Gardie, Sophie Couve, Emmanuel Donnadieu, Sophie Ferlicot, Catherine Richon, Thouraya Ben Safta, Arash Nanbakhsh, Katy Billot, Elodie Viry, Véronique Baud, Marie Boutet, Andrés Tittarelli, Bassam Janji, Meriem Hasmim, Muhammad Zaeem Noman, and Yosra Messai

Abstract

Supplemental video 1. 786-0 cells described in Figure 3B were recorded by time-lapse video microscopy

Published
2023
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18. Supplementary Tables 1 - 7 and Figures 1 - 3 from Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis

Author

Betty Gardie, Stéphane Richard, Peter Ratcliffe, William Kaelin, David R. Mole, Luba Tchertanov, Philippe Dessen, Nathalie M. Mazure, Anne-Paule Gimenez-Roqueplo, Vladimir Lazar, Jean Feunteun, Brigitte Bressac-de Paillerets, Patrick R. Benusiglio, Françoise Lasne, Christine Collin, Jean-Christophe Pagès, Bernard Lecomte, William Y. Kim, Gregory Nuel, Marion Le Gentil, Hélène Le Jeune, Sophie Gad, Justine Guégan, Karène Mahtouk, Elodie Laine, Charline Ladroue, and Sophie Couvé

Abstract

Table S1: Phenotypes associated with single R161Q and R200W VHL germline mutations are different from the phenotype associated with the combined mutations. Table S2: VHL mutations associated with polycythemia are different from the VHL mutations involved in severe von Hippel-Lindau disease. Table S3: Members of the family carrying the VHL-R200W+R161Q mutations present normal hematological values. Table S4: Intra-domain hydrogen bonds are severely destabilized by the mutations. Table S5: The double mutant reduced the inter-domain mobility compared to the single one. Table S6: The pVHL/HIF-2α direct target genes are deregulated with a significantly ascending gradient by the pVHL mutants of increased severity. Table S7: The target genes of the pVHL/HIF-2α axis that are deregulated in renal cell carcinoma play a role in oncogenic pathways. Figure S1: Germline mutations in the VHL gene are associated with distinct phenotypes. Figure S2: (A) The crystallographic structure of pVHL contains a seven-stranded β-sandwich connected to four α-helices by a flexible linker. (B) The R200W mutation dramatically weakens hydrogen bonds established in the wild-type form between Arg200 and Glu134, and between Arg197 and Arg120. (C) The R161Q mutation indirectly influences crucial stabilizing interactions involving primarily Arg 167. Figure S3: VHL mRNA expression is equivalent in 786.O cells transduced by the different VHL inducible lentiviral constructs.

Published
2023
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19. Supplementary Data from Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis

Author

Betty Gardie, Stéphane Richard, Peter Ratcliffe, William Kaelin, David R. Mole, Luba Tchertanov, Philippe Dessen, Nathalie M. Mazure, Anne-Paule Gimenez-Roqueplo, Vladimir Lazar, Jean Feunteun, Brigitte Bressac-de Paillerets, Patrick R. Benusiglio, Françoise Lasne, Christine Collin, Jean-Christophe Pagès, Bernard Lecomte, William Y. Kim, Gregory Nuel, Marion Le Gentil, Hélène Le Jeune, Sophie Gad, Justine Guégan, Karène Mahtouk, Elodie Laine, Charline Ladroue, and Sophie Couvé

Abstract

Supplementary Material and Methods and Legend of Supplementary Tables and Figures

Published
2023
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20. Mutation of the proline P81 into a serine modifies the tumour suppressor function of the von Hippel-Lindau gene in the ccRCC

Author

Franck Chesnel, Emmanuelle Jullion, Olivier Delalande, Anne Couturier, Adrien Alusse, Xavier Le Goff, Marion Lenglet, Betty Gardie, Caroline Abadie, Yannick Arlot-Bonnemains, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Institut du Thorax [Nantes], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, LNCC for financial support of this study., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and École pratique des hautes études (EPHE)

Subjects
Cancer Research, [SDV.GEN]Life Sciences [q-bio]/Genetics, Oncology, Proline, Von Hippel-Lindau Tumor Suppressor Protein, Serine, Mutation, Missense, Humans, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Carcinoma, Renal Cell, Kidney Neoplasms
Abstract

International audience; BACKGROUND: The von Hippel-Lindau disease is an autosomal dominant syndrome associated with tumour formation in various tissues, such as retina, central nervous system, kidney, and adrenal glands. VHL gene deletion or mutations support the development of various cancers. Unclassified VHL variants also referred as "of unknown significance" result from gene mutations that have an unknown or unclear effect on protein functions. The P81S mutation has been linked to low penetrance Type 1 disease but its pathogenic function was not clearly determined. METHODS: We established a stable cell line expressing the pVHL(213) (c.241C>T, P81S) mutant. Using biochemical and physiological approaches, we herein analysed pVHL folding, stability and function in the context of this VHL single missense mutation. RESULTS: The P81S mutation mostly affects the non-canonical function of the pVHL protein. The cells expressing the pVHL(213)P81S acquire invasive properties in relation with modified architecture network. CONCLUSION: We demonstrated the pathogenic role of this mutation in tumour development in vhl patients and confirm a medical follow up of family carrying the c.241C>T, P81S.

Published
2022
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21. Involvement of PBRM1 in VHL disease‑associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway

Author

Virginie Verkarre, Sophie Couvé, Guillaume Meurice, Betty Gardie, Bin Tean Teh, Baptiste Nguyen, Flore Renaud, Stéphane Richard, Sophie Ferlicot, Bastien Job, Melanie Da Costa, Benjamin Grandon, Véronique Duchatelle, Nathalie Droin, Sophie Gad, Vincent Molinié, Katia Posseme, Gwénaël Le Teuff, and Arnaud Mejean

Subjects
polybromo 1 somatic mutation, BAF180, Cancer Research, endocrine system diseases, Tumor suppressor gene, Oncogene, Cancer, von Hippel-Lindau disease, Articles, clear cell renal cell carcinoma, Biology, urologic and male genital diseases, medicine.disease, female genital diseases and pregnancy complications, PBRM1, Clear cell renal cell carcinoma, Von Hippel-Lindau germline mutation, Germline mutation, Oncology, Hypoxia-inducible factors, medicine, Cancer research, hypoxia inducible factor 1, hypoxia inducible factor 2, Von Hippel–Lindau disease
Abstract

Von Hippel-Lindau (VHL) disease is the main cause of inherited clear-cell renal cell carcinoma (ccRCC) and is caused by germline mutations in the VHL tumor suppressor gene. Bi-allelic VHL alterations lead to inactivation of pVHL, which plays a major role by downstream activation of the hypoxia inducible factor (HIF) pathway. Somatic VHL mutations occur in 80% of sporadic ccRCC cases and the second most frequently mutated gene is polybromo 1 (PBRM1). As there is currently no data regarding PBRM1 involvement in VHL disease-associated ccRCC, the aim of the present study was to assess the PBRM1 mutational status, and PBRM1 and HIF expression in VHL disease-associated ccRCC series compared with a sporadic series. PBRM1 gene was screened by Sanger sequencing for 23 VHL-disease-associated ccRCC and 22 sporadic ccRCC cases. Immunohistochemical studies were performed to detect the expression of PBRM1, HIF1 and HIF2 for all cases. In VHL-associated tumors, 13.0% (n=3/23) had PBRM1 somatic mutations and 17.4% (n=4/23) had a loss of PBRM1 nuclear expression. In sporadic cases, 27.3% (n=6/22) showed PBRM1 somatic mutations and 45.5% (n=10/22) had a loss of PBRM1 nuclear expression. Loss of PBRM1 was associated with an advanced tumor stage. HIF1-positive tumors were observed more frequently in the VHL-associated ccRCC than in the sporadic series. Furthermore, in the VHL cohort, PBRM1 expression appeared to be associated more with HIF1 than with HIF2. Given that hereditary tumors tend to be less aggressive, these results would suggest that co-expression of PBRM1 and HIF1 may have a less oncogenic role in VHL-associated ccRCC.

Published
2021
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22. Diagnosis of exon 12‐positive polycythemia vera rescued by NGS

Author

Stéphane Bézieau, François Girodon, Fabrice Airaud, Bernard Aral, Valentin Bourgeois, Antoine Geay, Céline Garrec, Pauline Martin, and Betty Gardie

Subjects
lcsh:Medicine, Case Report, Case Reports, 030204 cardiovascular system & hematology, DNA sequencing, 03 medical and health sciences, Exon, 0302 clinical medicine, Polycythemia vera, Exon 12, polycythemia vera, hemic and lymphatic diseases, medicine, erythrocytosis, next generation sequencing, lcsh:R5-920, business.industry, Jak2 mutation, lcsh:R, General Medicine, medicine.disease, Virology, JAK2, 030220 oncology & carcinogenesis, business, lcsh:Medicine (General)
Abstract

A JAK2V617F‐negative polycythemia associated with low serum epo needs to be tested for an exon 12 JAK2 mutation. When negative, due to potential serious complications in PV, a next generation sequencing is necessary to rule out false negative results.

Published
2020

23. Low incidence of EPOR mutations in idiopathic erythrocytosis

Author

Cédric Le Maréchal, Stéphane Béziau, Céline Garrec, Fabrice Airaud, Aurélie Chauveau, Martin Gauthier, François Girodon, Aisha Bruce, Yann Polfrit, Eric Lippert, Betty Gardie, Mathilde Filser, Bernard Aral, and Anne Thiebaut

Subjects
Erythropoietin, business.industry, Incidence (epidemiology), Mutation (genetic algorithm), medicine, Idiopathic erythrocytosis, Hematology, business, Bioinformatics, Receptor, medicine.drug, Erythropoietin receptor
Published
2020
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24. Von Hippel Lindau (VHL) : classification de 187 variants du gène VHL par les 9 laboratoires français du groupe TENGEN (réseau oncogénétique des tumeurs neuroendocrines)

Author

C. Garrec, Y. Arlot, Alexandre Buffet, G. Mougel, Nelly Burnichon, Anne-Paule Gimenez-Roqueplo, Pascal Pigny, A. Mohamed, Frédérique Savagner, B. Bressac, Anne Barlier, Betty Gardie, S. Giraud, Stéphane Richard, and D. Prunier

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract

La maladie de VHL est une pathologie hereditaire responsable d’hemangioblastomes, de cancers du rein et de pheochromocytome lies a des mutations germinales du gene VHL. L’interpretation des variants faux-sens de ce gene reste problematique. Nous rapportons ici le travail de classification de 187 variants faux-sens de VHL chez 373 cas index, recueillis entre 2018 et 2021 dans les 9 laboratoires du reseau expert TENGEN et du reseau PREDIR. Une premiere classification etait effectuee par les laboratoires en suivant les recommandations de l’ACMG (American College of Medical Genetics) avant d’etre rediscutee par l’ensemble des experts au cours de reunions. Ces donnees ont ete enregistrees dans la base de donnees locus-specifique UMD-VHL (umd.be/VHL). La classification par expert a permis de reclasser 35 variants de signification inconnue (VSI): 28 d’entre eux en variant (probablement) pathogene et 7 en variant (probablement) benin. Le caractere pathogene a pu etre affirme pour 29 variants initialement classes comme probablement pathogene. Seul un variant present avant le codon 54 etait classe pathogene. Il s’agissait d’un variant situe dans le 5′UTR present dans 2 familles avec cosegregation genotype-phenotype chez 4 membres sur 5. Au total, cette classification par expert a modifie la prise en charge de 58 cas index porteurs de ces 35 variants initialement classes comme VSI, donc non utilisable comme test predictif pour les apparentes. Ces resultats mettent en evidence l’importance du recueil exhaustif des caracteristiques cliniques des patients dans la classification des variants de VHL ainsi que l’apport d’un travail collegial d’un groupe d’expert.

Published
2021
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25. Germline mutation in the NBR1 gene involved in autophagy detected in a family with renal tumors

Author

Katia Posseme, Sophie Giraud, Pauline Garnier, Bastien Job, Sophie Gad, Betty Gardie, Brigitte Bressac-de Paillerets, Stéphane Richard, Flore Renaud, Nathalie Droin, Virginie Verkarre, Florine Adolphe, Sophie Ferlicot, Marc Deloger, and Sophie Couvé

Subjects
Adult, Male, Cancer Research, Cell, Biology, urologic and male genital diseases, medicine.disease_cause, Germline, Frameshift mutation, Germline mutation, Genetics, medicine, Autophagy, Humans, Genetic Predisposition to Disease, Folliculin, Molecular Biology, Gene, Carcinoma, Renal Cell, Exome sequencing, Germ-Line Mutation, Aged, Mutation, Intracellular Signaling Peptides and Proteins, Middle Aged, Prognosis, female genital diseases and pregnancy complications, Kidney Neoplasms, Pedigree, medicine.anatomical_structure, Cancer research, Female, Follow-Up Studies
Abstract

Hereditary Renal Cell Carcinomas (RCC) are caused by mutations in predisposing genes, the major ones including VHL, FLCN, FH and MET. However, many families with inherited RCC have no germline mutation in these genes. Using Whole Exome Sequencing on germline DNA from a family presenting three different histological renal tumors (an angiomyolipoma, a clear-cell RCC and an oncocytic papillary RCC), we identified a frameshift mutation in the Neighbor of BRCA1 gene 1 (NBR1), segregating with the tumors. NBR1 encodes a cargo receptor protein involved in autophagy. Genetic and functional analyses suggested a pathogenic impact of the mutation. Indeed, functional study performed in renal cell lines showed that the mutation alters NBR1 interactions with some of its partners (such as p62/SQSTM1), leading to a dominant negative effect. This results in an altered autophagic process and an increased proliferative capacity in renal cell lines. Our study suggests that NBR1 may be a new predisposing gene for RCC, however its characterization needs to be further investigated in order to confirm its role in renal carcinogenesis.

Published
2020

27. Increased incidence of germline PIEZO1 mutations in individuals with idiopathic erythrocytosis

Author

Laurent Peres, Betty Gardie, Marlène Palach, Lydie Da Costa, Guillaume Bouyer, Patricia Aguilar Martinez, Véronique Picard, Céline Garrec, Mathilde Filser, François Girodon, Stéphane Egée, Bernard Aral, David Monedero Alonso, Muriel Giansily-Blaizot, Mélanie Grenier, Pierre Cougoul, Stéphane Bézieau, and Fabrice Airaud

Subjects
Adult, Male, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Incidence (epidemiology), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Cell Biology, Hematology, Polycythemia, Middle Aged, Biochemistry, Virology, Germline, Ion Channels, Cohort Studies, Young Adult, Mutation (genetic algorithm), Medicine, Humans, Idiopathic erythrocytosis, Female, business, Germ-Line Mutation
Published
2020

28. Can absolute polycythaemia be identified without measurement of the red cell mass?

Author

Jean Marc Riedinger, Mathilde Nughe, Betty Gardie, Davide Callegarin, François Girodon, and Mélanie Grenier

Subjects
Adult, Aged, 80 and over, Male, Pathology, medicine.medical_specialty, Polycythaemia, Hematologic Tests, Red Cell, Adolescent, business.industry, Hematology, Polycythemia, Middle Aged, medicine.disease, Young Adult, Medicine, Humans, business, Myeloproliferative neoplasm, Aged, Erythrocyte Volume
Published
2020

29. Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel- Lindau disease spectrum or with paraganglioma

Author

Caroline Dehais, Bruna Calsina, Anne Paule Gimenez-Roqueplo, Judith Favier, Brigitte Bressac-de Paillerets, Shahida K. Flores, Javier Aller, Stéphane Richard, Philippe Herman, Pauline Romanet, Peter Kamenický, Marion Lenglet, S. Giraud, Anne Barlier, Atanaska Elenkova, Sophie Lejeune, Betty Gardie, Alexandre Buffet, Mercedes Robledo, Elisa Deflorenne, María Calatayud, J.-L. Sadoul, Erwan De Mones Del Pujol, Isabelle Bourdeau, Nelly Burnichon, Patricia L. M. Dahia, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Spanish National Cancer Research Center (CNIO), The University of Texas at San Antonio (UTSA), Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hospital Universitario Puerta de Hierro, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hospital Universitario 12 de Octubre [Madrid], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Medical University of Sofia [Bulgarie], Hôpital Lariboisière-Fernand-Widal [APHP], Hôpital Bicêtre, CHU Lille, Service d'endocrinologie [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité de recherche de l'institut du thorax (ITX-lab), romanet, pauline, École Pratique des Hautes Études (EPHE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM], and Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)

Subjects
0301 basic medicine, Oncology, Male, von Hippel-Lindau Disease, endocrine system diseases, urologic and male genital diseases, Germline, 0302 clinical medicine, Paraganglioma, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Exons, Middle Aged, female genital diseases and pregnancy complications, cryptic exon, 3. Good health, Pedigree, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Cohort, Female, Adult, medicine.medical_specialty, Pheochromocytoma, 03 medical and health sciences, Young Adult, Germline mutation, Internal medicine, Genetics, medicine, Cancer Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, Von Hippel–Lindau disease, neoplasms, Germ-Line Mutation, Genetic testing, Aged, business.industry, medicine.disease, 030104 developmental biology, business, von Hippel-Lindau, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BackgroundsThe incidence of germline mutations in the newly discovered cryptic exon (E1’) of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known.MethodsWe studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum (‘Single VHL tumour’ cohort), 70 patients with multiple tumours of the VHL spectrum (‘Multiple VHL tumours’ cohort), 76 patients with a VHL disease as described in the literature (‘VHL-like’ cohort) and 946 patients with a PPGL were screened for E1’ genetic variants.ResultsSix different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (pConclusionsVHL E1’ cryptic exon mutations contribute to 1.32% (1/76) of ‘VHL-like’ cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.

Published
2020
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30. Importance of Sequencing HBA1, HBA2 and HBB Genes to Confirm the Diagnosis of High Oxygen Affinity Hemoglobin

Author

Mathilde Filser, Betty Gardie, Mathieu Wemeau, Patricia Aguilar-Martinez, Muriel Giansily-Blaizot, and François Girodon

Subjects
Adult, Male, HBB, Adolescent, Genotype, high oxygen affinity hemoglobin, erythrocytosis, next generation sequencing, P50, HBA1, HBA2, Polycythemia, QH426-470, Article, Hemoglobins, Young Adult, Genetics, Humans, Hemoglobin A2, Child, Genetics (clinical), Aged, Retrospective Studies, Aged, 80 and over, Glycated Hemoglobin, Middle Aged, Oxygen, Mutation, Female
Abstract

High oxygen affinity hemoglobin (HOAH) is the main cause of constitutional erythrocytosis. Mutations in the genes coding the alpha and beta globin chains (HBA1, HBA2 and HBB) strengthen the binding of oxygen to hemoglobin (Hb), bringing about tissue hypoxia and a secondary erythrocytosis. The diagnosis of HOAH is based upon the identification of a mutation in HBA1, HBA2 or HBB in specialized laboratories. Phenotypic studies of Hb are also useful, but electrophoretic analysis can be normal in 1/3 of cases. The establishment of the dissociation curve of Hb can be used as another screening test, a shift to the left indicating an increased affinity for Hb. The direct measurement of venous P50 using a Hemox Analyzer is of great importance, but due to specific analytic conditions, it is only available in a few specialized laboratories. Alternatively, an estimated measurement of the P50 can be obtained in most of the blood gas analyzers on venous blood. The aim of our study was therefore to determine whether a normal venous P50 value could rule out HOAH. We sequenced the HBB, HBA1 and HBA2 genes of 75 patients with idiopathic erythrocytosis. Patients had previously undergone an exhaustive medical check-up after which the venous P50 value was defined as normal. Surprisingly, sequencing detected HOAH in three patients (Hb Olympia in two patients, and Hb St Nazaire in another). A careful retrospective examination of their medical files revealed that (i) one of the P50 samples was arterial; (ii) there was some air in another sample; and (iii) the P50 measurement was not actually done in one of the patients. Our study shows that in real life conditions, due to pre-analytical contingencies, a venous P50 value that is classified as being normal may not be sufficient to rule out a diagnosis of HOAH. Therefore, we recommend the systematic sequencing of the HBB, HBA1 and HBA2 genes in the exploration of idiopathic erythrocytosis.

Published
2022
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31. Absence of CALR Mutations in Idiopathic Erythrocytosis Patients with Low Serum Erythropoietin Levels

Author

Mary Frances McMullin, Amy Graham, François Girodon, Sophie Laird, Betty Gardie, Céline Garrec, Robert J. G. Cuthbert, Mark Catherwood, and Nicholas C.P. Cross

Subjects
medicine.medical_specialty, Serum erythropoietin, biology, Erythrocyte indices, business.industry, Hematology, General Medicine, 03 medical and health sciences, Disease susceptibility, 0302 clinical medicine, Endocrinology, Erythropoietin, 030220 oncology & carcinogenesis, Internal medicine, Mutation (genetic algorithm), biology.protein, medicine, Idiopathic erythrocytosis, business, Calreticulin, 030215 immunology, medicine.drug
Published
2018
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32. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome

Author

Wallid Deb, Bertrand Cariou, Arnaud Wiedemann, Julien Thevenon, Rhonda E. Schnur, Vincent Ramaekers, Alexandre N. Datta, Richard Redon, Solène Conrad, Natacha Sloboda, Benjamin Cogné, François Feillet, Geneviève Baujat, Bertrand Isidor, Pierre Vabres, Tawfeg Ben-Omran, Marie Vincent, Flora Breheret, Dorothea Wand, Aline Delignières, Laurence Faivre, Betty Gardie, Xavier Balguerie, Anne-Claire Bursztejn, Marion Lenglet, Lionel Van Maldergem, Sébastien Küry, Antonin Lamaziere, Virginie Carmignac, Eva Trochu, Sébastien Barbarot, Marie-Cécile Nassogne, Erin Torti, Yue Si, Paul Kuentz, Thomas Besnard, Jean-Louis Guéant, Alice Goldenberg, Stéphane Bézieau, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, Hamad medical corporation, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Basel (Unibas), Hôpital Bretagne Atlantique, Partenaires INRAE, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre Hospitalier Universitaire de Liège (CHU-Liège), Gene Dx, Centre de Génétique, and Hôpital St-Antoine

Subjects
Male, Developmental Disabilities, Intellectual disability, cholesterol pathway, Whole Exome Sequencing, chemistry.chemical_compound, Missense mutation, Age of Onset, Child, Intramolecular Transferases, Genetics (clinical), Exome sequencing, Genetics, Sanger sequencing, 0303 health sciences, biology, Lanosterol, 030305 genetics & heredity, LSS, 3. Good health, Pedigree, Cholesterol, Phenotype, intellectual disability, Child, Preschool, Allelic Imbalance, Congenital cataracts, symbols, Female, Squalene, early-onset epileptic encephalopathy, 03 medical and health sciences, symbols.namesake, Cholesterol pathway, Exome Sequencing, medicine, Humans, 030304 developmental biology, Epilepsy, Infant, Alopecia, alopecia, medicine.disease, Early-onset epileptic encephalopathy, chemistry, Mutation, biology.protein, Hypotrichosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Lanosterol synthase
Abstract

International audience; Purpose Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. Methods Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. Results We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. Conclusion In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.

Published
2019
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33. High HFE mutation incidence in idiopathic erythrocytosis

Author

François Girodon, Stéphane Bézieau, Céline Garrec, Betty Gardie, Céline Buriller, Valentin Bourgeois, Bénédicte Burlet, Bernard Aral, and Fabrice Airaud

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, Incidence (epidemiology), Incidence, Hematology, Polycythemia, Gastroenterology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Mutation (genetic algorithm), Mutation, medicine, Humans, Idiopathic erythrocytosis, business, Hemochromatosis Protein
Published
2018

34. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease

Author

Mathias Vilaine, Céline Garrec, Pierre Lindenbaum, Sophie Couvé, Mathilde Pacault, Laurence Heidet, Stéphane Bézieau, Celeste Bento, David Hoogewijs, Helene Dreau, Yannick Arlot-Bonnemains, Nelly Burnichon, Marion Lenglet, Richard van Wijk, Maria-Luigia Randi, Alexandre Buffet, Florence Robriquet, Fabrice Airaud, Holger Cario, Nicolas Janin, Melissa M. Pentony, Erika Kvikstad, Stéphane Richard, Karim Bouchireb, Antonis Kattamis, Jean-Michaël Mazzella, Carme Camps, Sylvie Job, Sophie Ferlicot, Anne Couturier, Richard Redon, Maria Caterina Putti, Thomas Besnard, Joachim R. Göthert, Klaus-Michael Debatin, Betty Gardie, Sophie Deveaux, Franck Chesnel, Solenne Dumont, Jenny C. Taylor, Marine Cornec, Bin Tean Teh, François Girodon, Vincent Bours, Sophie Gad, Anne-Paule Gimenez-Roqueplo, Sabine Irtan, Klaus Schwarz, Elpis Mantadakis, Samantha J. L. Knight, Brigitte Bressac-de Paillerets, Molecular Mechanisms of Chronic Inflammation in Hematological Diseases (CRCINA-ÉQUIPE 16), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Universität Ulm - Ulm University [Ulm, Allemagne], Institute for Clinical Transfusion Medicine and Immunogenetics [Ulm, Germany], German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen, University of Oxford, Oxford NIHR Biomedical Research Centre, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Fribourg = University of Fribourg (UNIFR), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5), Immunologie intégrative des tumeurs (UMR 1186), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Oxford University Hospitals NHS Trust, Centre de Références Cancers Rares (PREDIR), INCA, Hôpital Bicêtre, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Hôpitaux Universitaires Paris-Sud Bicêtre (APHP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Sorbonne Paris Cité (USPC), Democritus University of Thrace (DUTH), Universitätsklinikum Ulm - University Hospital of Ulm, Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris-Saclay, National Heart Centre Singapore (NHCS), Service d'hématologie biologique [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, laboratory of Excellence GR-Ex, Paris, France, Università degli Studi di Padova = University of Padua (Unipd), C.H.U. Sart Tilman [Liège], University Medical Center [Utrecht], University Hospital [Essen, Germany], National and Kapodistrian University of Athens (NKUA), Cliniques Universitaires Saint-Luc [Bruxelles], Centro Hospitalar e Universitário [Coimbra], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Zürich Center for Integrative Human Physiology (ZIHP), Universität Zürich [Zürich] = University of Zurich (UZH)-Institute of Physiology, Faculté de Médecine, Université de Ngozi, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Oncologique [Villejuif], École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Department of Medicine, Karolinska Institutet [Stockholm], National Haemoglobinopathy Reference Laboratory, Molecular Haematology, Haemophilia Centre, Churchill Hospital, John Radcliffe Hospital [Oxford University Hospital], Centre Expert National Cancer Rares PREDIR, Service d'Urologie, CHU de Bicêtre, Le Kremlin-Bicêtre, Service Genetique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d’Anatomie Cytologie Pathologiques, Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris (AP-HP), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Pediatrics and Adolescent Medicine, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie et pathologie médicales [Gustave Roussy], Van Andel Research Institute, Grand Rapids, Michigan, Van Andel Institute [Grand Rapids], Service d'hématologie biologique (CHU de Dijon), Utrecht University [Utrecht], First Department of Paediatrics, Athens University, Thalassaemia Unit, 'Aghia Sofia' Children's Hospital, Centre Hospitalier Universitaire de Liège (CHU-Liège), SAFRAN Group, Service Génétique, Union nationale des coopératives d’élevage et d’insémination animale (UNCEIA), Rare Adrenal Cancer Network COMETE, CHATEL, Stephanie, University of Fribourg, and UCL - (SLuc) Centre de génétique médicale UCL

Subjects
0301 basic medicine, Adult, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Heterozygote, von Hippel-Lindau Disease, Adolescent, endocrine system diseases, Biochemistry, Immunology, Hematology, Cell Biology, RNA Splicing, [SDV]Life Sciences [q-bio], Medizin, Polycythemia, Biology, medicine.disease_cause, urologic and male genital diseases, 03 medical and health sciences, Exon, Young Adult, medicine, Humans, Genetic Predisposition to Disease, Von Hippel–Lindau disease, Child, Gene, neoplasms, Genetics, Mutation, Intron, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Exons, Middle Aged, medicine.disease, Exon skipping, female genital diseases and pregnancy complications, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], 030104 developmental biology, Von Hippel-Lindau Tumor Suppressor Protein, RNA splicing, Female, Synonymous substitution
Abstract

International audience; Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with von Hippel-Lindau disease, which is characterized by the development of highly vascularized tumors. Here, we identified a new VHL cryptic-exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identified mutations in E1' in seven families with erythrocytosis (one homozygous case and six compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in one large family with typical VHL disease but without any alteration in the other VHL exons. In this study we have shown that the mutations induced a dysregulation of the VHL splicing with excessive retention of E1' and are associated with a downregulation of VHL protein expression. In addition, we have demonstrated a pathogenic role for synonymous mutations in VHL-Exon 2 that alter splicing through E2-skipping in five families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially impact splicing, correlating with phenotype severity. This study demonstrates that cryptic-exon-retention or exon-skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research into the VHL-related-hypoxia-signaling pathway.

Published
2018
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35. Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease

Author

Sophie Couvé, Nathalie Droin, Sophie Giraud, Virginie Verkarre, Mathieu Chiquet, Sophie Gad, Brigitte Bressac-De-Paillerets, Philippe Dessen, Betty Gardie, Viorel Vasiliu, Stéphane Richard, Bin Tean Teh, Arnaud Mejean, Sophie Ferlicot, Charles-Henry Gattolliat, Cedric Orear, Vincent Molinié, and Guillaume Meurice

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, von Hippel-Lindau Disease, Tumor suppressor gene, Biology, Kidney, urologic and male genital diseases, Neoplasms, Multiple Primary, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Cell Line, Tumor, microRNA, medicine, Humans, miRNA and mRNA profiling, RNA, Messenger, Von Hippel–Lindau disease, Carcinoma, Renal Cell, Aged, Oligonucleotide Array Sequence Analysis, Aged, 80 and over, Regulation of gene expression, Gene Expression Profiling, Cancer, Articles, Middle Aged, medicine.disease, Molecular medicine, Kidney Neoplasms, clear-cell renal cell carcinoma, Gene Expression Regulation, Neoplastic, Gene expression profiling, MicroRNAs, 030104 developmental biology, Oncology, Von Hippel-Lindau Tumor Suppressor Protein, Case-Control Studies, 030220 oncology & carcinogenesis, Cancer research, Female, Neoplasm Recurrence, Local, integrative analyses
Abstract

Von Hippel-Lindau (VHL) disease is a rare auto-somal dominant syndrome that is the main cause of inherited clear-cell renal cell carcinoma (ccRCC), which generally occurs in the form of multiple recurrent synchronized tumors. Affected patients are carriers of a germline mutation in the VHL tumor suppressor gene. Somatic mutations of this gene are also found in sporadic ccRCC and numerous pan-genomic studies have reported a dysregulation of microRNA (miRNA) expression in these sporadic tumors. In order to investigate the molecular mechanisms underlying the pathogenesis of VHL-associated ccRCC, particularly in the context of multiple tumors, the present study characterized the mRNA and miRNA transcriptome through an integrative analysis compared with sporadic renal tumors. In the present study, two series of ccRCC samples were used. The first set consisted of several samples from different tumors occurring in the same patient, for two independent patients affected with VHL disease. The second set consisted of 12 VHL-associated tumors and 22 sporadic ccRCC tumors compared with a pool of normal renal tissue. For each sample series, an expression analysis of miRNAs and mRNAs was conducted using microarrays. The results indicated that multiple tumors within the kidney of a patient with VHL disease featured a similar pattern of miRNA and gene expression. In addition, the expression levels of miRNA were able to distinguish VHL-associated tumors from sporadic ccRCC, and it was identified that 103 miRNAs and 2,474 genes were differentially expressed in the ccRCC series compared with in normal renal tissue. The majority of dysregulated genes were implicated in 'immunity' and 'metabolism' pathways. Taken together, these results allow a better understanding of the occurrence of ccRCC in patients with VHL disease, by providing insights into dysregulated miRNA and mRNA. In the set of patients with VHL disease, there were few differences in miRNA and mRNA expression, thus indicating a similar molecular evolution of these synchronous tumors and suggesting that the same molecular mechanisms underlie the pathogenesis of these hereditary tumors.

Published
2018
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36. Identification of a new

Author

Marion, Lenglet, Florence, Robriquet, Klaus, Schwarz, Carme, Camps, Anne, Couturier, David, Hoogewijs, Alexandre, Buffet, Samantha J L, Knight, Sophie, Gad, Sophie, Couvé, Franck, Chesnel, Mathilde, Pacault, Pierre, Lindenbaum, Sylvie, Job, Solenne, Dumont, Thomas, Besnard, Marine, Cornec, Helene, Dreau, Melissa, Pentony, Erika, Kvikstad, Sophie, Deveaux, Nelly, Burnichon, Sophie, Ferlicot, Mathias, Vilaine, Jean-Michaël, Mazzella, Fabrice, Airaud, Céline, Garrec, Laurence, Heidet, Sabine, Irtan, Elpis, Mantadakis, Karim, Bouchireb, Klaus-Michael, Debatin, Richard, Redon, Stéphane, Bezieau, Brigitte, Bressac-de Paillerets, Bin Tean, Teh, François, Girodon, Maria-Luigia, Randi, Maria Caterina, Putti, Vincent, Bours, Richard, Van Wijk, Joachim R, Göthert, Antonis, Kattamis, Nicolas, Janin, Celeste, Bento, Jenny C, Taylor, Yannick, Arlot-Bonnemains, Stéphane, Richard, Anne-Paule, Gimenez-Roqueplo, Holger, Cario, and Betty, Gardie

Subjects
Adult, Male, Heterozygote, von Hippel-Lindau Disease, Adolescent, RNA Splicing, Exons, Polycythemia, Middle Aged, Pedigree, Young Adult, Von Hippel-Lindau Tumor Suppressor Protein, Mutation, Humans, Female, Genetic Predisposition to Disease, Child
Abstract

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (

Published
2018

37. Update on hypoxia-inducible factors and hydroxylases in oxygen regulatory pathways: from physiology to therapeutics

Author

Lisa Oliver, Peter J. Ratcliffe, Betty Gardie, Jiannis Ragoussis, Peppi Koivunen, Valérie Trichet, Claire Vinatier, Ines Batinic-Haberle, Judith V.M.G. Bovée, Johanna Myllyharju, Florence Robriquet, The Francis Crick Institute, Target Discovery Institute [Oxford, UK], University of Oxford [U.K.], Oulu Center for Cell-Matrix Research [Oulu, Finland], Biocenter Oulu and Faculty of Biochemistry & Molecular Medicine [Oulu, Finland]-University of Oulu [Finland], McGill University, Montréal (McGill University) ( McGill ), Department of Pathology [Leiden, The Netherlands], Leiden University Medical Center (LUMC), Duke university [Durham], Regenerative Medicine and Skeleton research lab ( RMeS ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), École pratique des hautes études ( EPHE ), The meeting 'Hypoxia Nantes 2106' (https://hypoxia.univ-nantes.fr) was financially supported by Alliance Bio Expertise, Baker Ruskinn, the Région Pays de la Loire, project 'ERRATA' and 'EryCan', Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051, Nantes University, and Dove Press., ANR-11-IDEX-0005-02/11-LABX-0051,GR-Ex,Biogenèse et pathologies du globule rouge ( 2011 ), Target Discovery Institute [Oxford, UK] (TDI), University of Oxford [Oxford], The Francis Crick Institute [London], Genome Quebec Innovation Centre [Montréal, Canada], McGill University = Université McGill [Montréal, Canada], Department of Radiation Oncology [Durham, NC, USA], Duke University Medical Center, Université de Nantes - UFR Odontologie, Université de Nantes (UN), Team STEP 'Skeletal physiopathology and joint regenerative medicine' (Inserm U1229 - RMeS), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), University of Oxford, RMeS - Skeletal Physiopathology and Joint Regenerative Medicine (RMeS-REJOINT), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Jehan, Frederic, and Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID

Subjects
0301 basic medicine, Physiology, Review, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, lipid metabolism, medicine, genomics, cancer, oxidative stress, lcsh:R5-920, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, musculoskeletal, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, hypoxia, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Hypoxia (medical), 3. Good health, Oxidative stress, 030104 developmental biology, Hypoxia-inducible factors, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, medicine.symptom, Large group, lcsh:Medicine (General)
Abstract

Peter Ratcliffe,1,2 Peppi Koivunen,3 Johanna Myllyharju,3 Jiannis Ragoussis,4 Judith VMG Bovée,5 Ines Batinic-Haberle,6 Claire Vinatier,7 Valérie Trichet,8 Florence Robriquet,9 Lisa Oliver,9 Betty Gardie9,10 1Target Discovery Institute, University of Oxford, 2The Francis Crick Institute, London, UK; 3Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; 4McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, Canada; 5Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; 6Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA; 7INSERM UMR 1229, Regenerative Medicine and Skeleton-RMeS, Team STEP, University of Nantes, UFR Odontology, 8UMR 1238 INSERM, Université de Nantes, Faculté de Médecine, 9CRCINA, INSERM, Université de Nantes, Nantes, 10Ecole Pratique des Hautes Etudes, PSL Research University, Paris, France Abstract: The “Hypoxia Nantes 2016” organized its second conference dedicated to the field of hypoxia research. This conference focused on “the role of hypoxia under physiological conditions as well as in cancer” and took place in Nantes, France, in October 6–7, 2016. The main objective of this conference was to bring together a large group of scientists from different spheres of hypoxia. Recent advances were presented and discussed around different topics: genomics, physiology, musculoskeletal, stem cells, microenvironment and cancer, and oxidative stress. This review summarizes the major highlights of the meeting. Keywords: hypoxia, genomics, lipid metabolism, musculoskeletal, cancer, oxidative stress&nbsp

Published
2017
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38. Gene panel sequencing in idiopathic erythrocytosis

Author

Betty Gardie, Céline Garrec, François Girodon, Fabrice Airaud, Stéphane Bézieau, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université Paris-Dauphine, PSL Research University, Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), université de Bourgogne, LNC, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Letter, Genetic testing, MEDLINE, Polycythemia, Biology, Idiopathic erythrocytosis, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, Gene panel, medicine, Humans, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Online Only Articles, Exome sequencing, Genetics, Genetic syndromes, Genetic Variation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Sequence Analysis, DNA, Hematology, Gene panel sequencing, medicine.disease, 030104 developmental biology, Molecular Diagnostic Techniques, Mutation, 030215 immunology
Abstract

Erythrocytosis is a rare disorder characterized by increased red cell mass and elevated hemoglobin concentration and hematocrit. Several genetic variants have been identified as causes for erythrocytosis in genes belonging to different pathways including oxygen sensing, erythropoiesis and oxygen transport. However, despite clinical investigation and screening for these mutations, the cause of disease cannot be found in a considerable number of patients, who are classified as having idiopathic erythrocytosis. In this study, we developed a targeted next-generation sequencing panel encompassing the exonic regions of 21 genes from relevant pathways (~79 Kb) and sequenced 125 patients with idiopathic erythrocytosis. The panel effectively screened 97% of coding regions of these genes, with an average coverage of 450×. It identified 51 different rare variants, all leading to alterations of protein sequence, with 57 out of 125 cases (45.6%) having at least one of these variants. Ten of these were known erythrocytosis-causing variants, which had been missed following existing diagnostic algorithms. Twenty-two were novel variants in erythrocytosis-associated genes (EGLN1, EPAS1, VHL, BPGM, JAK2, SH2B3) and in novel genes included in the panel (e.g. EPO, EGLN2, HIF3A, OS9), some with a high likelihood of functionality, for which future segregation, functional and replication studies will be useful to provide further evidence for causality. The rest were classified as polymorphisms. Overall, these results demonstrate the benefits of using a gene panel rather than existing methods in which focused genetic screening is performed depending on biochemical measurements: the gene panel improves diagnostic accuracy and provides the opportunity for discovery of novel variants.

Published
2017
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39. The role of PHD2 mutations in the pathogenesis of erythrocytosis

Author

Joanne Ewing, Stéphane Richard, Frank S. Lee, Rasheduzzaman Chowdhury, Celeste Bento, Frédéric Lambert, Patrick R. Arsenault, Mary Frances McMullin, Melanie J. Percy, Helena Almeida, Betty Gardie, David Hoogewijs, Christopher J. Schofield, and University of Zurich

Subjects
Genetics, biology, hypoxia, Nonsense mutation, 610 Medicine & health, Review, 10052 Institute of Physiology, Frameshift mutation, Germline mutation, 10076 Center for Integrative Human Physiology, Oxygen homeostasis, biology.protein, erythrocytosis, 570 Life sciences, Missense mutation, PHD2, HIF, erythropoietin, Hypoxia, Haploinsufficiency, Transcription factor, EGLN1
Abstract

The transcription of the erythropoietin (EPO) gene is tightly regulated by the hypoxia response pathway to maintain oxygen homeostasis. Elevations in serum EPO level may be reflected in an augmentation in the red cell mass, thereby causing erythrocytosis. Studies on erythrocytosis have provided insights into the function of the oxygen-sensing pathway and the critical proteins involved in the regulation of EPO transcription. The α subunits of the hypoxia-inducible transcription factor are hydroxylated by three prolyl hydroxylase domain (PHD) enzymes, which belong to the iron and 2-oxoglutarate-dependent oxygenase superfamily. Sequence analysis of the genes encoding the PHDs in patients with erythrocytosis has revealed heterozygous germline mutations only occurring in Egl nine homolog 1 (EGLN1, also known as PHD2), the gene that encodes PHD2. To date, 24 different EGLN1 mutations comprising missense, frameshift, and nonsense mutations have been described. The phenotypes associated with the patients carrying these mutations are fairly homogeneous and typically limited to erythrocytosis with normal to elevated EPO. However, exceptions exist; for example, there is one case with development of concurrent paraganglioma (PHD2-H374R). Analysis of the erythrocytosis-associated PHD2 missense mutations has shown heterogeneous results. Structural studies reveal that mutations can affect different domains of PHD2. Some are close to the hypoxia-inducible transcription factor α/2-oxoglutarate or the iron binding sites for PHD2. In silico studies demonstrate that the mutations do not always affect fully conserved residues. In vitro and in cellulo studies showed varying effects of the mutations, ranging from mild effects to severe loss of function. The exact mechanism of a potential tumor-suppressor role for PHD2 still needs to be elucidated. A knockin mouse model expressing the first reported PHD2-P317R mutation recapitulates the phenotype observed in humans (erythrocytosis with inappropriately normal serum EPO levels) and demonstrates that haploinsufficiency and partial deregulation of PHD2 is sufficient to cause erythrocytosis., Video abstract

Published
2014

40. Von Hippel–Lindau: How a rare disease illuminates cancer biology

Author

Sophie Couvé, Betty Gardie, Stéphane Richard, Sophie Gad, Institut National du Cancer [Boulogne Billancourt] (INC), Laboratoire de Génétique Oncologique [Villejuif], École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
Cancer Research, Pathology, medicine.medical_specialty, von Hippel-Lindau Disease, endocrine system diseases, Angiogenesis, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuroendocrine tumors, Biology, urologic and male genital diseases, Targeted therapy, 03 medical and health sciences, Rare Diseases, Targeted therapies, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Renal cell carcinoma, Neoplasms, medicine, Animals, Humans, HIF, neoplasms, Genetic Association Studies, Germ-Line Mutation, 030304 developmental biology, 0303 health sciences, Cilium, medicine.disease, Penetrance, female genital diseases and pregnancy complications, 3. Good health, Disease Models, Animal, Von Hippel–Lindau, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Rare disease
Abstract

International audience; Von Hippel–Lindau (VHL) disease is a rare autosomal dominant syndrome (1/36,000 live births) with highly penetrance that predispose to the development of a panel of highly vascularized tumors (model of tumoral angiogenesis). Main manifestations include central nervous system (CNS) and retinal haeman-gioblastomas, endolymphatic sac tumors, clear-cell renal cell carcinomas (RCC), phaeochromocytomas and pancreatic neuroendocrine tumors. RCC has become the first potential cause of mortality and VHL disease is the main cause of inherited RCC. The disease is caused by germline mutations in the VHL tumor-suppressor gene that plays a major role in regulation of the oxygen-sensing pathway by targeting the hypoxia-inducible factor HIF for degradation in proteasome. VHL has also major HIF-independent functions , specially in regulation of primary cilium, extracellular matrix and apoptosis. Somatic inactivation of the VHL gene is the main molecular event in most sporadic RCC and the treatment of advanced RCC has been revolutionized by targeted therapy with drugs that block angiogenesis. These drugs are now in first line in metastatic sporadic RCC and have shown promising results for RCC, pancreatic neuroendocrine tumors and malignant pheochromocytomas in VHL patients.

Published
2013
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41. Corrigendum: A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Author

Olivier Caron, Etienne Rouleau, Hamida Mohamdi, F. Boitier, Jean-Luc Perrot, Eve Maubec, Arnaud de la Fouchardière, Stéphane Richard, Pierre Vabres, Luc Thomas, Rosette Lidereau, Simon Saule, Diana Zelenika, Pilar Galan, Tanguy Martin-Denavit, Lorenza Pastorino, N. Poulalhon, Jérôme Couturier, Bruno Labeille, Eve Corda, Caroline Robert, Philippe Dessen, Marie-Françoise Avril, Bernard Escudier, Christian Ingvar, Sandy Giuliano, Celia Badenas, Robert Ballotti, Benoit d’Hayer, Gilbert M. Lenoir, Betty Gardie, Stéphane Dalle, Laurence Brugières, Brigitte Bressac-de Paillerets, Audrey Remenieras, Valérie Chaudru, Paola Ghiorzo, Hélène Blanché, Philippe Bahadoran, Fabienne Lesueur, Håkan Olsson, Bin Tean Teh, Philippe Vielh, Corine Bertolotto, Pascale Andry-Benzaquen, Thomas Strub, Florence Demenais, Vincent Molinié, Mahaut de Lichy, Susana Puig, Karine Bille, Sophie Gad, Annick Rossi, Mark Lathrop, Nicolas Dupin, Irwin Davidson, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Mutation, Multidisciplinary, Melanoma, Carcinoma, SUMO protein, Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, medicine.disease, Microphthalmia-associated transcription factor, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Germline mutation, medicine, Cancer research, Epigenetics, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract

Nature 480, 94–98 (2011); doi:10.1038/nature10539 In this Letter, one image was mistakenly duplicated during preparation of the artwork. In the original Fig. 3d, the left image illustrating migration of RCC4 cells transduced with empty adenovirus (EV) at 24 h is a duplicate of the middle image showing migration of RCC4 cells transduced with an adenovirus encoding Mi-WT.

Published
2016
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42. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Author

Romain Carcenac, Michel Leporrier, Stéphane Richard, Michel Barrois, Jean-Jacques Kiladjian, Jacques Pouysségur, André Baruchel, Nathalie M. Mazure, David Hoogewijs, Roland H. Wenger, Anne-Paule Gimenez-Roqueplo, Charline Ladroue, Brigitte Bressac-de Paillerets, Nicole Casadevall, Jean Feunteun, Betty Gardie, Sophie Gad, Fadi Fakhoury, Olivier Hermine, Federica Storti, Bernardo, Elizabeth, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Zürich Center for Integrative Human Physiology (ZIHP), Universität Zürich [Zürich] = University of Zurich (UZH)-Institute of Physiology, Service de Génétique [Villejuif], Institut Gustave Roussy (IGR), Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hematopoïese et cellules souches normales et pathologiques (U790), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigations Cliniques, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Département de Néphrologie [CHU Necker], Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Expert National Cancers Rares INCa 'PREDIR' and Réseau National INCa [AP-HP Hôpital Bicêtre, Paris], Service d'urologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This work was supported by grants from the 'Association pour la Recherche sur le Cancer' (ARC), the French National Cancer Institute ('INCa', PNES Rein, and Réseau National Prédispositions héréditaires au cancer du rein) and the French Ligue Nationale contre le Cancer (Comités du Cher et de l’Indre) as well as by the HypoxiaNet COST Action TD0901. DH is supported by a postdoctoral Marie Curie IEF Fellowship from the European Commission and the Sassella Stiftung. DH and RHW are supported by grants from the State Secretariat of Education and Research (C10.0106) and from the NCCR Kidney.CH, funded by the SNF., Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Zürich Center for Integrative Human Physiology ( ZIHP ), University of Zürich [Zürich] ( UZH ) -Institute of Physiology, Institut Gustave Roussy ( IGR ), Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires ( LRI - EA4062 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service d'Hématologie Clinique, CHU Caen-Hôpital Clémenceau, Hematopoïese et cellules souches normales et pathologiques ( U790 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Stabilité Génétique et Oncogenèse ( UMR 8200 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de signalisation, biologie du développement et cancer ( ISBDC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre-Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Adult, Male, hypoxia inducible factor, Adolescent, Tumor suppressor gene, Mutant, Procollagen-Proline Dioxygenase, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polycythemia, Biology, medicine.disease_cause, Germline, Hypoxia-Inducible Factor-Proline Dioxygenases, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Hydroxylation, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, erythrocytosis, medicine, Humans, PHD2, Cells, Cultured, Germ-Line Mutation, hypoxia-inducible transcription factor, 030304 developmental biology, 0303 health sciences, Base Sequence, Hydrolysis, Original Articles, Hematology, Middle Aged, Hypoxia (medical), Hypoxia-Inducible Factor 1, alpha Subunit, Molecular biology, 3. Good health, HEK293 Cells, chemistry, Hypoxia-inducible factors, 030220 oncology & carcinogenesis, Female, Mutant Proteins, medicine.symptom, Carcinogenesis
Abstract

International audience; BACKGROUND: Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma.DESIGN AND METHODS: Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively.RESULTS: This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category.CONCLUSIONS: As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.

Published
2011
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43. A study of 36 unrelated cases with pure erythrocytosis revealed three new mutations in the erythropoietin receptor gene

Author

Frédéric Galactéros, Betty Gardie, Valérie Ugo, Nicole Casadevall, Michel Goossens, Elodie Mazurier, Henri Wajcman, Maha Al-Sheikh, and Claude Préhu

Subjects
Adult, Male, Adolescent, Procollagen-Proline Dioxygenase, Polycythemia, Biology, medicine.disease_cause, Hypoxia-Inducible Factor-Proline Dioxygenases, Frameshift mutation, Exon, Receptors, Erythropoietin, medicine, Humans, Child, Gene, Aged, Genetics, Mutation, Janus kinase 2, Hematology, Middle Aged, Molecular biology, Stop codon, Erythropoietin receptor, Gene Expression Regulation, Von Hippel-Lindau Tumor Suppressor Protein, biology.protein, Female, Variants of PCR
Abstract

Thirty-six unrelated cases with erythrocytosis of unknown origin were investigated. Exons 5-8 of the erythropoietin receptor gene (EPOR), the von Hippel-Lindau gene, and the prolyl hydroxylase domain protein 2 gene (PHD2) were screened by direct DNA sequencing. The Janus kinase 2 mutation, JAK2 (Val617Phe), was screened by allele specific PCR. In this study, three new mutations of EPOR causing deletions in exon 8 were found: the first led directly to a stop codon [g.5957_5958delTT (p.Phe424X)], the second to a stop codon after one residue [g.5828_5829delCC (p.Pro381GlnfsX1)] and the third to a stop codon following a frameshift sequence of 23 residues [g.5971delC (p.Leu429TrpfsX23)]. One patient had a previously reported EPOR mutation [g.6146A>G (p.Asn487Ser)] and another, a silent one (g.5799G>A). All were heterozygotes. In addition, 2 patients were positive for JAK2 (Val617Phe), and 2 reported elsewhere, were mutated in the PHD2 gene [c.606delG (p.Met202IlefsX71).

Published
2008
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44. Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion

Author

Betty Gardie, Catherine L Olsen, Martha R. Stampfer, and Paul Yaswen

Subjects
Senescence, Cancer Research, Telomerase, Cell type, Gene Conversion, Biology, medicine.disease_cause, Transduction (genetics), p14arf, Genetics, medicine, Telomerase reverse transcriptase, Breast, Molecular Biology, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Cyclin, Cell Cycle, Epithelial Cells, Cell biology, DNA-Binding Proteins, Proto-Oncogene Proteins c-raf, body regions, Cell Transformation, Neoplastic, Carcinogenesis
Abstract

Using an estrogen-inducible retroviral system, we demonstrate that oncogenic Raf-1 induces growth arrest and morphological changes in finite lifespan human mammary epithelial cells (HMEC). This arrest does not rely on expression of the cyclin-dependent kinase inhibitor (CKI) p16(INK4a), nor on changes in expression of the CKIs p21(Cip1), p14(ARF), p27(Kip1) or p57(Kip2). The Raf-induced arrest is independent of viral oncogene mediated inactivation of p53 and pRB, or c-myc overexpression. Flow cytometric analysis demonstrates that cells arrest in both G1 and G2. The Raf-induced arrest is mitigated or eliminated in some immortally transformed HMEC. Immortal HMEC that have both overcome replicative senescence and undergone the recently described conversion process maintain growth in the presence of transduced oncogenic Raf-1; they also gain EGF-independent growth and a low frequency of anchorage-independent growth. However, HMEC that have overcome replicative senescence but have not undergone conversion and HMEC immortalized by transduction with the catalytic subunit of telomerase, hTERT, remain severely growth arrested. These results indicate that the molecular mechanisms responsible for the Raf-1-induced growth arrest may vary among different finite lifespan cell types, and that in HMEC, this mechanism is altered during the conversion process, rather than as a direct consequence of overcoming senescence or expressing hTERT.

Published
2002
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45. Transgenic Expression of the p16INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4−CD8− Immature Thymocytes

Author

Stéphanie Eyquem, Betty Gardie, Chantal Lagresle, Marika Pla, Jean-Christophe Bories, Magali Fasseu, Jean-Claude Vieville, and François Sigaux

Subjects
CD4-Positive T-Lymphocytes, CD3 Complex, T-Lymphocytes, T cell, CD3, Immunology, Apoptosis, Mice, Transgenic, Thymus Gland, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Antibodies, Mice, Cyclin-dependent kinase, medicine, Animals, Humans, Immunology and Allergy, IL-2 receptor, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Mice, Knockout, biology, Nuclear Proteins, Cell Differentiation, Receptors, Antigen, T-Cell, gamma-delta, Cell cycle, Molecular biology, DNA-Binding Proteins, Thymocyte, medicine.anatomical_structure, T cell differentiation, biology.protein, RNA, CD8, HeLa Cells, Signal Transduction
Abstract

In the thymus, T cell development proceeds by successive steps of differentiation, expansion, and selection. Control of thymocyte proliferation is critical to insure the full function of the immune system and to prevent T cells from transformation. Deletion of the cell cycle inhibitor p16INK4a is frequently observed in human T cell neoplasias and, in mice, gene targeted inactivation of the Ink4a locus enhances thymocyte expansion and predisposes mutant animal to tumorigenesis. Here, we investigate the mechanism by which p16Ink4a controls thymocyte development by analyzing transgenic mice expressing the human p16INK4a into the T cell lineage. We show that forced expression of p16INK4a in thymocytes blocked T cell differentiation at the early CD4−CD8−CD3−CD25+ stage without significantly affecting the development of γδ T cells. Pre-TCR function was mimicked by the induction of CD3 signaling in thymocytes of recombinase activating gene (RAG)-2-deficient mice (RAG-2−/−). Upon anti-CD3ε treatment in vivo, p16INK4a-expressing RAG-2−/− thymocytes were not rescued from apoptosis, nor could they differentiate. Our data demonstrate that expression of p16INK4a prevents the pre-TCR-mediated expansion and/or survival of differentiating thymocytes.

Published
2002
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46. Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis

Author

Sophie Couvé, Hélène Le Jeune, David R. Mole, Karène Mahtouk, Gregory Nuel, Peter J. Ratcliffe, Anne Paule Gimenez-Roqueplo, Justine Guegan, Françoise Lasne, William G. Kaelin, Nathalie M. Mazure, Charline Ladroue, Jean Christophe Pagès, William Y. Kim, Patrick R. Benusiglio, Luba Tchertanov, Stéphane Richard, Brigitte Bressac-de Paillerets, Marion Le Gentil, Vladimir Lazar, Elodie Laine, Philippe Dessen, Betty Gardie, Christine Collin, Jean Feunteun, Sophie Gad, Bernard Lecomte, Institut National du Cancer [Boulogne Billancourt] (INC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Génomique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Lineberger Comprehensive Cancer Center (UNC Lineberger), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Médecine générale, Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours-EA3856, Agence Française de Lutte contre le Dopage (AFLD), Institut Gustave Roussy (IGR), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Angiogenesis Imaging UMR970, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Henry Wellcome Building for Molecular Physiology, University of Oxford [Oxford], Howard Hughes Medical Institute (HHMI), Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by grants from the Ligue Nationale contre le Cancer (Comites du Cher et de l'Indre, de la Loire Atlantique et des Cotes d'Armor), the French NCI (INCa, PNES 'Kidney cancer'), the 'Association pour la Recherche sur le Cancer' (ARC), the 'Association VHL France,' the Region Pays de la Loire, as well as by the HypoxiaNet COST Action TD0901. S. Couve was supported by postdoctoral fellowships from the Fondation 'Cancer, Aidez la recherche!' and the 'Fondation Gustave Roussy.'The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact., Bernardo, Elizabeth, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-EA3856, Université Nice Sophia Antipolis (1965 - 2019) (UNS), University of Oxford, Institut National du Cancer [Boulogne Billancourt] ( INC ), École pratique des hautes études ( EPHE ), Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology ( LCQB ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Plateforme de génomique, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Mathématiques Appliquées à Paris 5 ( MAP5 - UMR 8145 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National des Sciences Mathématiques et de leurs Interactions-Centre National de la Recherche Scientifique ( CNRS ), Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Agence Française de Lutte contre le Dopage ( AFLD ), Institut Gustave Roussy ( IGR ), Service de Génétique, Institut de cancérologie Gustave Roussy, Villejuif, France, Stabilité Génétique et Oncogenèse ( UMR 8200 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Recherche sur le Cancer et le Vieillissement ( IRCAN ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Howard Hugues Medical Institute, Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, École Pratique des Hautes Études (EPHE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Pathology, medicine.medical_specialty, endocrine system diseases, Carcinogenesis, Mutant, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pheochromocytoma, Biology, Molecular Dynamics Simulation, medicine.disease_cause, Compound heterozygosity, urologic and male genital diseases, Polymorphism, Single Nucleotide, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Malignant transformation, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Gene, neoplasms, Carcinoma, Renal Cell, 030304 developmental biology, 0303 health sciences, medicine.disease, Phenotype, female genital diseases and pregnancy complications, Kidney Neoplasms, 3. Good health, Oncology, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Mutation, Cancer research, Signal Transduction
Abstract

The classic model of tumor suppression implies that malignant transformation requires full “two-hit” inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a “continuum” model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the “continuum” model of tumor suppression. Cancer Res; 74(22); 6554–64. ©2014 AACR.

Published
2014
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47. ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy

Author

Elodie Viry, Muhammad Zaeem Noman, Laurence Albiges, Jerome Thiery, Thouraya Ben Safta, Catherine Richon, Véronique Baud, Yosra Messai, Andrés Tittarelli, Florence Orlanducci, Bassam Janji, Katy Billot, Emmanuel Donnadieu, Marie Boutet, Sophie Ferlicot, Salem Chouaib, Meriem Hasmim, Daniel Olive, Betty Gardie, Sophie Couvé, Arash Nanbakhsh, and Bernard Escudier

Subjects
Cancer Research, Cell, urologic and male genital diseases, Mice, Cell Line, Tumor, medicine, Autophagy, Basic Helix-Loop-Helix Transcription Factors, Gene silencing, Animals, Humans, Inositol 1,4,5-Trisphosphate Receptors, Receptor, Carcinoma, Renal Cell, Mice, Inbred BALB C, Innate immune system, business.industry, Membrane Proteins, female genital diseases and pregnancy complications, Kidney Neoplasms, Gene Expression Regulation, Neoplastic, Killer Cells, Natural, medicine.anatomical_structure, Oncology, Cell culture, Cancer cell, Immunology, Cancer research, Beclin-1, business, Apoptosis Regulatory Proteins, Transcriptome, Chromatin immunoprecipitation
Abstract

Clear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia-inducible factors (HIF). In this study, we investigated the potential role of HIF2α in regulating RCC susceptibility to natural killer (NK) cell–mediated killing. We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared with the VHL-corrected cell line (WT7). This resistance was found to require HIF2α stabilization. On the basis of global gene expression profiling and chromatin immunoprecipitation assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF2α and that targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Mechanistically, HIF2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK-mediated killing through the activation of autophagy in target cells by NK-derived signal. Interestingly, both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Our data provide insight into the link between HIF2α, the ITPR1-related pathway, and natural immunity and strongly suggest a role for the HIF2α/ITPR1 axis in regulating RCC cell survival. Cancer Res; 74(23); 6820–32. ©2014 AACR.

Published
2014

48. NovelFHmutation in a patient with cutaneous leiomyomatosis associated with cutis verticis gyrata, eruptive collagenoma and Charcot-Marie-Tooth disease

Author

Stéphane Richard, Pierre Rustin, Bernard Guillot, B. Bressac de Paillerets, M. Marque, Betty Gardie, and Didier Bessis

Subjects
Mutation, Pathology, medicine.medical_specialty, business.industry, Dermatology, Disease, medicine.disease, medicine.disease_cause, Central nervous system disease, Degenerative disease, Leiomyomatosis, Eruptive Collagenoma, Fumarase, medicine, Cutis verticis gyrata, business
Abstract

Multiple cutaneous and uterine leiomyomatosis (MCUL)/hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM 150800/OMIM 605839) is a rare hereditary disorder leading to the development of benign cutaneous and uterine smooth muscle tumours in young adults. 1,2 This disease is characterized by an increased risk of developing renal cell carcinomas. 3 It results from dominantly inherited autosomal mutations in the fumarate hydratase (FH) gene. 4 This gene encodes a Krebs cycle enzyme, present in both cytosolic and mitochondrial compartments, and probably acts as a tumour suppressor gene. We report a 22-year-old man affected by cutaneous leiomyomatosis associated with cutis verticis gyrata, disseminated collagenoma and Charcot-Marie-Tooth disease, who was harbouring the novel FH gene mutation c.821C > T, p.Ala274Val.

Published
2010
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49. Genomic Alterations of the p19ARF Encoding Exons in T-Cell Acute Lymphoblastic Leukemia

Author

Jean-Michel Cayuela, Sophie Martini, François Sigaux, and Betty Gardie

Subjects
Adult, Male, Adolescent, Tumor suppressor gene, Immunology, Locus (genetics), Thymus Gland, Biology, Polymerase Chain Reaction, Biochemistry, Exon, Tumor Suppressor Protein p14ARF, Humans, Leukemia-Lymphoma, Adult T-Cell, RNA, Messenger, Allele, Child, Gene, Alleles, Recombination, Genetic, Genetics, Recombinase activity, Proteins, RNA-Directed DNA Polymerase, Gene rearrangement, Cell Biology, Hematology, Cell cycle, Blotting, Southern, Female, Gene Deletion
Abstract

We have previously shown that the disruption/deletion of the MTS(MTS1-MTS2) locus due to illegitimate V(D)J recombinase activity is a genetic event characteristic of T-cell acute lymphoblastic leukemia (T-ALL). Inactivation of the p16INK4a tumor suppressor protein, encoded by MTS1, is thought to be the major functional consequence of these chromosomal rearrangements. The two other cell cycle inhibitors encoded by genes identified in the locus (p19ARF by MTS1 and p15INK4b by MTS2), also represent possible candidates for inactivating events. By analyzing p16INK4aexpression in three cases in which an identical 36-kb deletion had deleted MTS2 and disrupted the p19ARF, but spared the p16INK4aMTS1 encoding exons, we have excluded p16INK4a and pinpointed p19ARF and/or p15INK4b as the functional target(s) of this rearrangement. Moreover, by the study of the MTS genomic configuration of 149 rearranged alleles from a large series of T-ALL cases, we have shown that p19ARF encoding exons were always disrupted or deleted, whereas p16INK4a and p15INK4b encoding exons were spared in four and 21 cases, respectively. These results suggest that p19ARF may be targeted by the genetic events that occur in the MTS locus in the majority of T-ALLs.

Published
1998
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50. Identification of TET1 Partners That Control Its DNA-Demethylating Function

Author

Fiona LePape, Arulraj Nadaradjane, François M. Vallette, Lisenn Lalier, Betty Gardie, and Pierre-François Cartron

Subjects
Genetics, Cancer Research, biology, EZH2, Short Report, Methylation, MECP2, Cell biology, Proliferating cell nuclear antigen, chemistry.chemical_compound, chemistry, DNA methylation, Cancer cell, biology.protein, DNA, Demethylation
Abstract

Several recent reports have identified TET1 as the main enzyme modulating DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. However, little is known about the protein network that controls TET1 activity. By using a new proximity ligation in situ assay, we identified MeCP2, HDAC1/6/7, EZH2, mSin3A, PCNA, and LSD1 as TET1-interacting proteins. We also discerned that TET1/PCNA acts as a demethylator of the cyclical methylation/demethylation process, the perturbation of which promotes the aberrant methylation hallmarks frequently observed in cancer cells.

Published
2013

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