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1. Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency

Author

Marie-Thérèse El-Daher, Julie Lemale, Julie Bruneau, Claire Leveau, Frédéric Guerin, Nathalie Lambert, Jean-Sébastien Diana, Bénédicte Neven, Fernando E. Sepulveda, Aurore Coulomb-L'Hermine, Thierry Molina, Capucine Picard, Alain Fischer, and Geneviève de Saint Basile

Subjects
tetratricopeptide repeat domain 7A, lymphoproliferative syndrome, intestinal pseudo-obstruction, fsn mouse, mutant's cell phenotype, Immunologic diseases. Allergy, RC581-607
Abstract

Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we report the clinical, biological and molecular features of a patient born from consanguineous parents, presenting with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO). Genetic screening revealed the novel c.974G>A (p.R325Q) mutation in homozygosity in the TTC7A gene. The patient's phenotype differs significantly from that previously associated with TTC7A deficiency in humans. It becomes closer to the one reported in the ttc7a-deficient mice that invariably develop a proliferative lymphoid and myeloid disorder. Functional studies showed that the extreme variability in the clinical phenotype couldn't be explained by the cellular phenotype. Indeed, the patient's TTC7A mutation, as well as the murine-ttc7 mutant, have the same functional impact on protein expression, DNA instability and chromatin compaction, as the other mutations that lead to classical TTC7A-associated phenotypes. Co-inheritance of genetic variants may also contribute to the unique nature of the patient's phenotype. The present case report shows that the clinical spectrum of TTC7A deficiency is much broader than previously suspected. Our findings should alert the physicians to consider screening of TTC7A mutations in patients with lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction.

Published
2019
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2. GC content but not nucleosome positioning directly contributes to intron-splicing efficiency in Paramecium

Author

Olivier Arnaiz, Frédéric Guerin, Sandra Duharcourt, Mélody Matelot, Mireille Bétermier, Claude Thermes, Marion Weiman, Stefano Gnan, Chun-Long Chen, Linda Sperling, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Institut Jacques Monod (IJM (UMR_7592)), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
0303 health sciences, biology, [SDV]Life Sciences [q-bio], Intron, Computational biology, biology.organism_classification, Genome, Chromatin, 03 medical and health sciences, 0302 clinical medicine, RNA splicing, Nucleosome, Paramecium tetraurelia, Paramecium, 030217 neurology & neurosurgery, GC-content, 030304 developmental biology
Abstract

Eukaryotic genes are interrupted by introns that must be accurately spliced from mRNA precursors. With an average length of 25 nt, the >90,000 introns of Paramecium tetraurelia stand among the shortest introns reported in eukaryotes. The mechanisms specifying the correct recognition of these tiny introns remain poorly understood. Splicing can occur co-transcriptionally and it has been proposed that chromatin structure might influence splice site recognition. To investigate the roles of nucleosome positioning in intron recognition, we determined the nucleosome occupancy along the P. tetraurelia genome. We showed that P. tetraurelia displays a regular nucleosome array with a nucleosome repeat length of ∼151 bp, amongst the smallest periodicities reported. Our analysis revealed that introns are frequently associated with inter-nucleosomal DNA, pointing to an evolutionary constraint to locate introns at the AT-rich nucleosome edge sequences. Using accurate splicing efficiency data from cells depleted for the nonsense-mediated decay effectors, we showed that introns located at the edge of nucleosomes display higher splicing efficiency than those at the centre. However, multiple regression analysis indicated that the GC content, rather than nucleosome positioning, directly contributes to intron splicing efficiency. Our data reveal a complex link between GC content, nucleosome positioning and intron evolution in Paramecium.

Published
2021

3. Massive colonization of protein-coding exons by selfish genetic elements in Paramecium germline genomes

Author

Karine Labadie, Olivier Arnaiz, Simran Bhullar, Linda Sperling, Arnaud Couloux, Eric Meyer, Jean-Marc Aury, Diamantis Sellis, Sophie Malinsky, Nicole Boggetto, Emmanuelle Lerat, Laurent Duret, Sascha Krenek, Frédéric Guerin, Sandra Duharcourt, Walker Pett, Thomas U. Berendonk, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Eléments transposables, évolution, populations, Département génétique, interactions et évolution des génomes [LBBE] (GINSENG), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), ANR-18-CE12-0005,LaMarque,Transitions évolutives dans la reconnaissance du 'soi' génomique: petits ARN, facteurs spécifiques de séquence et méthylation de l'ADN(2018), ANR-19-CE12-0015,POLYCHROME,Complexe Polycomb chez la paramécie: interaction avec la machinerie des petits ARN et spécificité de substrats(2019), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Lerat, Emmanuelle, Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Iowa State University (ISU), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut für Hydrobiologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Evolutionary Genetics, Paramecium, [SDV]Life Sciences [q-bio], Protozoan Proteins, Gene Expression, Ciliate Protozoans, Genome, Germline, chemistry.chemical_compound, Database and Informatics Methods, 0302 clinical medicine, Mobile Genetic Elements, Gene expression, Biology (General), Paramecium aurelia, Data Management, Genetics, Protozoans, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, Macronucleus, General Neuroscience, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Eukaryota, Exons, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Phylogenetics, 030220 oncology & carcinogenesis, Horizontal gene transfer, Paramecium tetraurelia, General Agricultural and Biological Sciences, Sequence Analysis, Research Article, Transposable element, Computer and Information Sciences, Multiple Alignment Calculation, Gene Transposition, Bioinformatics, QH301-705.5, [SDV.MP.PRO] Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, Research and Analysis Methods, Genome Complexity, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, 03 medical and health sciences, Genetic Elements, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Computational Techniques, [SDV.BID.EVO] Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Animals, Domestic Animals, Evolutionary Systematics, Parasite Evolution, Ciliophora, Gene, 030304 developmental biology, Taxonomy, Ciliate, Evolutionary Biology, General Immunology and Microbiology, Transposable Elements, Intron, Organisms, Biology and Life Sciences, Computational Biology, biology.organism_classification, Primer, Introns, Split-Decomposition Method, Germ Cells, chemistry, Evolutionary biology, DNA Transposable Elements, Parasitology, Paramecium caudatum, Mobile genetic elements, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome, Protozoan, Zoology, Sequence Alignment, DNA
Abstract

Ciliates are unicellular eukaryotes with both a germline genome and a somatic genome in the same cytoplasm. The somatic macronucleus (MAC), responsible for gene expression, is not sexually transmitted but develops from a copy of the germline micronucleus (MIC) at each sexual generation. In the MIC genome of Paramecium tetraurelia, genes are interrupted by tens of thousands of unique intervening sequences called internal eliminated sequences (IESs), which have to be precisely excised during the development of the new MAC to restore functional genes. To understand the evolutionary origin of this peculiar genomic architecture, we sequenced the MIC genomes of 9 Paramecium species (from approximately 100 Mb in Paramecium aurelia species to >1.5 Gb in Paramecium caudatum). We detected several waves of IES gains, both in ancestral and in more recent lineages. While the vast majority of IESs are single copy in present-day genomes, we identified several families of mobile IESs, including nonautonomous elements acquired via horizontal transfer, which generated tens to thousands of new copies. These observations provide the first direct evidence that transposable elements can account for the massive proliferation of IESs in Paramecium. The comparison of IESs of different evolutionary ages indicates that, over time, IESs shorten and diverge rapidly in sequence while they acquire features that allow them to be more efficiently excised. We nevertheless identified rare cases of IESs that are under strong purifying selection across the aurelia clade. The cases examined contain or overlap cellular genes that are inactivated by excision during development, suggesting conserved regulatory mechanisms. Similar to the evolution of introns in eukaryotes, the evolution of Paramecium IESs highlights the major role played by selfish genetic elements in shaping the complexity of genome architecture and gene expression., A comparative genomics study of nine Paramecium species reveals successful invasion of genes by transposable elements in their germline genomes, showing that the internal eliminated sequences (IESs) followed an evolutionary trajectory remarkably similar to that of spliceosomal introns.

Published
2021

4. Differentiation of Spiral Ganglion Neurons from Human Dental Pulp Stem Cells: A Further Step towards Autologous Auditory Nerve Recovery

Author

Yassine Messat, Marta Martin-Fernandez, Said Assou, Keshi Chung, Frederic Guérin, Csilla Gergely, Frederic Cuisinier, and Azel Zine

Subjects
adult dental pulp stem cells, differentiation, human otic neural progenitors, spiral ganglion neurons, mechanical properties, cell therapy, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The degeneration of spiral ganglion neurons (SGNs), which convey auditory signals from hair cells to the brain, can be a primary cause of sensorineural hearing loss (SNHL) or can occur secondary to hair cell loss. Emerging therapies for SNHL include the replacement of damaged SGNs using stem cell-derived otic neuronal progenitors (ONPs). However, the availability of renewable, accessible, and patient-matched sources of human stem cells is a prerequisite for successful replacement of the auditory nerve. In this study, we derived ONP and SGN-like cells by a reliable and reproducible stepwise guidance differentiation procedure of self-renewing human dental pulp stem cells (hDPSCs). This in vitro differentiation protocol relies on the modulation of BMP and TGFβ pathways using a free-floating 3D neurosphere method, followed by differentiation on a Geltrex-coated surface using two culture paradigms to modulate the major factors and pathways involved in early otic neurogenesis. Gene and protein expression analyses revealed efficient induction of a comprehensive panel of known ONP and SGN-like cell markers during the time course of hDPSCs differentiation. Atomic force microscopy revealed that hDPSC-derived SGN-like cells exhibit similar nanomechanical properties as their in vivo SGN counterparts. Furthermore, spiral ganglion neurons from newborn rats come in close contact with hDPSC-derived ONPs 5 days after co-culturing. Our data demonstrate the capability of hDPSCs to generate SGN-like neurons with specific lineage marker expression, bipolar morphology, and the nanomechanical characteristics of SGNs, suggesting that the neurons could be used for next-generation cochlear implants and/or inner ear cell-based strategies for SNHL.

Published
2024
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5. Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis

Author

Fernando E. Sepulveda, Alain Fischer, Geneviève de Saint Basile, Romain Lévy, Mathieu Fusaro, Bénédicte Neven, Frédéric Guerin, Ahmed Chetouani, Despina Moshous, Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))

Subjects
0301 basic medicine, Ruxolitinib, Panniculitis, Cyclophosphamide, Lymphoma, T-Cell, Lymphohistiocytosis, Hemophagocytic, 03 medical and health sciences, 0302 clinical medicine, Subcutaneous Panniculitis-Like T-Cell Lymphoma, hemic and lymphatic diseases, Nitriles, medicine, Humans, Myelofibrosis, ComputingMilieux_MISCELLANEOUS, Hemophagocytic lymphohistiocytosis, business.industry, Hematology, medicine.disease, 3. Good health, Lymphoma, Transplantation, 030104 developmental biology, Pyrimidines, 030220 oncology & carcinogenesis, Immunology, Prednisolone, [SDV.IMM]Life Sciences [q-bio]/Immunology, Pyrazoles, Exceptional Case Report, business, medicine.drug
Abstract

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a distinct subset of cutaneous lymphomas in which neoplastic cytotoxic α/β CD8+ T cells infiltrate subcutaneous adipose tissue.1-3 SPTCL may affect both children and adults.4 Systemic symptoms such as fever, asthenia, and weight loss, associated with cytopenias and liver dysfunction, are common. In addition, hemophagocytic lymphohistiocytosis (HLH) is observed in 20% of cases,3 which is associated with poor prognosis and may be the leading cause of death.3 There is no standardized therapy for SPTCL alone or in association with HLH. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone is frequently used, with an overall remission rate of 50%.1 Immunosuppressive regimens, particularly cyclosporine A (CsA), may be also effective.5 In some severe cases, stem cell transplantation has been attempted.1 Recently, germline mutations causing loss of function of T-cell immunoglobulin mucin 3 (TIM-3) were identified in 60% to 85% of SPTCL patients.6,7 In these patients, TIM-3 deficiency was shown to promote T-lymphocyte and -macrophage activation and the production of proinflammatory cytokines, challenging the malignant nature of skin T-lymphocyte infiltration.6 Ruxolitinib is a selective JAK1/JAK2 inhibitor licensed for treatment of myelofibrosis and polycythemia vera in adults.8,9 Studies in animal models of HLH support the efficacy of this drug to prevent and treat HLH in these models.10,11 Anecdotal experiences of successful use of ruxolitinib to control refractory primary HLH or secondary HLH are also reported in humans.12-19 JAK1/JAK2 inhibitors are also increasingly used in inflammatory diseases. We herein report the use and efficacy of ruxolitinib in a patient with recurrence of SPTCL and HLH and in whom TIM-3 deficiency was recently identified.6

Published
2020

6. Germline TIM-3 Mutations Characterize Sub-Cutaneous Panniculitis T-Cell Lymphomas with Hemophagocytic Lymphohistiocytic Syndrome

Author

Simon Gravel, Sylvie Fraitag, Janie Charlebois, Jacek Majewski, Catherine Thieblemont, Rachel Conyers, Brigitte Bader-Meunier, Patrick Nitschke, Tenzin Gayden, Nada Jabado, Fernando E. Sepulveda, Paul G Ekert, Andrea Bajic, Mikko Taipale, Geneviève de Saint Basile, Daniel Schramek, Benedicte Neven, Jean-Sebastien Diana, Dong-Anh Khuong-Quang, Alain Fischer, David Michonneau, David Mitchell, Dzana Dervovic, Frank Sicheri, Maxime Battistella, Elvis Terci Valera, Alexandrine Garrigue, Stéphane Blanche, Despina Moshous, Hamid Nikbakht, Christopher McCormack, Rola Dali, Marianne Besnard, Jonathan Pratt, Nancy Hamel, Sharon Abish, Susan Kelso, H. Miles Prince, Christine Bole-Feysot, Van-Hung Nguyen, Frédéric Guerin, Leonie G. Mikael, William D. Foulkes, The University of MelbourneParkville, VIC, Australia., McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Sao Paulo (Brazil), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto [Canada], Canadian Centre for Computational Genomics, Montreal, Canada, Sinai Health System, Toronto, Canada, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), McGill University Health Center [Montreal] (MUHC), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], The Royal Children's Hospital, Melbourne, Australia, Urgences pédiatriques, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France, parent, Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Medicine, University of Melbourne, Melbourne, Australia, Centre Hospitalier de Polynésie Française, Service d'immuno-hématologie pédiatrique [CHU Necker], Murdoch Children's Research Institute (MCRI), Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Human Genetics [Montréal], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University

Subjects
T cell, Immunology, Biochemistry, Germline, 03 medical and health sciences, 0302 clinical medicine, Immune system, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Hemophagocytic lymphohistiocytosis, Innate immune system, biology, business.industry, Cell Biology, Hematology, medicine.disease, Immune checkpoint, 3. Good health, Lymphoma, medicine.anatomical_structure, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, business, 030215 immunology
Abstract

Introduction Sub-cutaneous panniculitis T-cell lymphomas (SPTCL), a rare non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening activation of the immune system which adversely impacts survival. T-cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. In this work we describe the first germline variants associated with SPTCL, which are in the TIM-3 gene. Methods We sequenced 27 SPTCL cases to identify gene variants. We performed TIM-3 functional analysis on immune cells from patients and HEK293 cells engineered to overexpress wild-type or mutant TIM-3. Results We identified homozygous, germline, loss-of-function, missense variants in highly conserved residues of TIM-3, namely p.Y82C and p.I97M in about 60% (16/27) of SPTCL cases. These samples were drawn from cases series across 3 continents. Patients with bi-allelic TIM-3 mutations were younger at diagnosis, and several had life-threatening HLH and severe disease course. TIM-3 mutations show specific geographic distribution. Y82C TIM-3 mutations occur on a founder chromosome in patients with East-Asian and Polynesian ancestry, while I97M TIM-3 is observed in Caucasians. Both variants induce protein misfolding and cytoplasmic retention of TIM-3. Loss of TIM-3 membrane expression in TIM-3 mutants abrogates the PD-1/PDL-1 checkpoint and prevents the termination of a Th1-immune response. In HEK293 cells, mutant TIM-3 was not expressed on the cell surface. Defective TIM-3 expression leads to persistent immune activation with increased production of inflammatory cytokines including TNF-alpha and IL-1beta by innate immune cells. Conclusion Our findings highlight HLH/SPTCL as a new genetic entity where loss of the TIM-3 immune checkpoint is associated with T-cell infiltration of adipose tissue and inflammasome activation. This is the first causative germline defect identified in SPTCL. While our findings indicate that TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint could have serious adverse consequences. Disclosures Prince: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Published
2019

7. Étude clinique à long terme et mutations HAVCR2 chez 70 patients atteints de lymphome T sous cutané à type de panniculite

Author

Nicolas Ortonne, Jean-David Bouaziz, A. de Masson, Christine Bodemer, F. Comoz, R. Kerdraon, Michel D'Incan, G. Bohelay, Liliane Laroche, F. Brunet-Possenti, Stéphane Barete, Pauline Brice, Nathalie Franck, G. de Saint-Basile, Sylvie Fraitag, I. Beschet, Eve Maubec, Caroline Ram-Wolff, Fernando E. Sepulveda, I. Brocheriou, S. Laurent-Roussel, C. Bléchet, Laurence Lamant, B. Balme, P. Moguelet, Ambroise Marçais, Marisa Battistella, S. Oro, David Michonneau, A. Finon, Frédéric Guerin, N. Bonnet, François Skowron, Olivier Dereure, Guy Leverger, Serge Boulinguez, Béatrice Vergier, Felipe Suarez, G. Sonigo, D. Haidar, Marie Beylot-Barry, Gérard Socié, R. Dubois, F. Le Gall, A. Mahe, G. Hervé, Agnès Carlotti, E. Tournier, L. Deschamps, G. Bens, S. Taix, S. Faiz, V. Costes-Martineau, Vanessa Szablewski, O. Carpentier, Henri Adamski, E. Birckel, Stéphane Dalle, F. Franck, O. Augereau, Jehane Fadlallah, Martine Bagot, and Olivia Boccara

Subjects
Dermatology
Abstract

Introduction Les lymphomes T sous-cutanes a type de panniculite (SPTCL, subcutaneous panniculitis T cell lymphoma) sont une forme rare de lymphome T cutane d’evolution classiquement indolente, neanmoins certains patients ont une evolution agressive dont les determinants sont mal connus. Une etude recente a identifie une mutation germinale de HAVCR2 (codant pour TIM-3, recepteur d’inhibiteur de checkpoint) dans des cas familiaux de SPTCL, notamment dans des populations asiatiques et de l’Ocean Pacifique. La prevalence de cette mutation dans les cas sporadiques n’est pas connue. Le but de cette etude etait de decrire les caracteristiques cliniques, histologiques et le suivi d’une large cohorte de SPTCL et d’etudier la prevalence des mutations HAVCR2 dans les formes sporadiques. Materiel et methodes Les cas ont ete identifies dans la base de donnees du GFELC, le diagnostic confirme par un pathologiste expert du GFELC. Les donnees cliniques, histologiques et l’evolution ont ete recueillies apres un suivi median de 35 mois (5jours-22 ans). La mutation de TIM-3 etait recherchee par sequencage sur le tissu tumoral ou sur le sang. Resultats 70 cas ont ete inclus (55 femmes) d’âge median de 42 ans (1–90 ans). 37 % avaient un antecedent d’auto-immunite, notamment de lupus (38 %). La presentation clinique la plus frequente etait celle de petits nodules (1–5 cm) sous-cutanes multiples situes aux membres. Soixante-huit pourcent avaient des signes B associes. Un syndrome d’activation macrophagique (SAM), etait trouve chez 12 patients (18 %), dont 5 formes graves (pris en charge en soins intensifs). Des auto-anticorps ont ete detecte chez 62 % des patients, notamment des anticorps anti-nucleaires (58 %) ( image 1 ). Chez 9 patients, une forme histologique frontiere avec une panniculite lupique etait trouvee. L’analyse PCR a revele une mutation HAVCR2 chez 10/49 (20 %) des patients presentant un materiel lesionnel approprie (caractere germinal confirme pour 6 patients), d’origine cambodgienne, vietnamienne, caledonienne, tahitienne, marocaine, algerienne et de l’ocean Indien (inconnue dans 2). Le SAM etait plus frequent (4/10 versus 5/39) et significativement plus grave (3/10 versus 0, p = 0,006) chez les patients mutes. La plupart des patients ont recu un traitement immunomodulateur en 1ere ligne (76,5 %; image 2 ); les patients atteints de SAM severe ont necessite une greffe autologue de cellules souches ou une chimiotherapie a base d’etoposide. Sur les 67 patients avec des donnees de suivi, 49 (73 %) etaient en reponse complete au dernier suivi, 32 % ont rechute (sans association significative avec une mutation de HAVCR2), 5 sont decedes, un (sans mutation de HAVCR2) de SPTCL. Conclusion Cette etude est la plus grande serie de SPTCL. Nos resultats mettent en evidence de rares mutations germinales de HAVCR2 dans le SPTCL sporadique, mais associees a des formes de SAM severe.

Published
2019

8. Universal trends of post-duplication evolution revealed by the genomes of 13 Paramecium species sharing an ancestral whole-genome duplication

Author

Jean-François Gout, Karine Labadie, Arnaud Couloux, Linda Sperling, Frédéric Guerin, Olivier Arnaiz, Thomas G. Doak, Sophie Malinsky, Parul Johri, Sandra Duharcourt, Eric Meyer, Michael Lynch, Simran Bhullar, Institut Jacques Monod (IJM (UMR_7592)), and Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0106 biological sciences, Whole genome sequencing, 0303 health sciences, Lineage (evolution), [SDV]Life Sciences [q-bio], Biology, biology.organism_classification, 01 natural sciences, Genome, 03 medical and health sciences, Evolutionary biology, Gene duplication, Paramecium tetraurelia, Paramecium, Gene, 030304 developmental biology, 010606 plant biology & botany, Segmental duplication
Abstract

Whole-Genome Duplications (WGDs) have shaped the gene repertoire of many eukaryotic lineages. The redundancy created by WGDs typically results in a phase of massive gene loss. However, some WGD-derived paralogs are maintained over long evolutionary periods and the relative contributions of different selective pressures to their maintenance is still debated. Previous studies have revealed a history of three successive WGDs in the lineage of the ciliateParamecium tetraureliaand two of its sister species from theP. aureliacomplex. Here, we report the genome sequence and analysis of 10 additionalP. aureliaspecies and one additional outgroup, allowing us to track post-WGD evolution in 13 species that share a common ancestral WGD. We found similar biases in gene retention compatible with dosage constraints playing a major role opposing post-WGD gene loss across all 13 species. Interestingly we found that post-WGD gene loss was slower inParameciumthan in other species having experienced genome duplication, suggesting that the selective pressures against post-WGD gene loss are especially strong inParamecium. We also report a lack of recent segmental duplications inParamecium, which we interpret as additional evidence for strong selective pressures against individual genes dosage changes. Finally, we hope that this exceptional dataset of 13 species sharing an ancestral WGD and two closely related outgroup species will be a useful resource for future studies and will help establishParameciumas a major model organism in the study of post-WGD evolution.

Published
2019
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9. Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency

Author

Claire Leveau, Bénédicte Neven, Fernando E. Sepulveda, Julie Lemale, Geneviève de Saint Basile, Jean-Sebastien Diana, Julie Bruneau, Capucine Picard, Thierry Jo Molina, Frédéric Guerin, Nathalie Lambert, Alain Fischer, Aurore Coulomb-L'Hermine, Marie-Thérèse El-Daher, Sepulveda, Fernando, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Signalisation, neurobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Arthrites autoimmunes (AA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U 132, Hôpital Necker - Enfants Malades, Paris, France, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pathologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Anatomie et Cytologie Pathologie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique Humaine des Maladies Infectieuses (Inserm U980), Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Institutes of Health and Medical Research (INSERM), la Fondation pour la Recherche Médicale (FRM project DEQ20150734354), the Imagine Foundation, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Chaire Médecine expérimentale (A. Fischer), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Intestinal pseudo-obstruction, Male, lcsh:Immunologic diseases. Allergy, Myeloid, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, fsn mouse, Case Report, medicine.disease_cause, 03 medical and health sciences, Consanguinity, Mice, 0302 clinical medicine, Immune system, Protein Deficiency, intestinal pseudo-obstruction, Immunology and Allergy, Medicine, Animals, Humans, Gene, Cells, Cultured, lymphoproliferative syndrome, Mutation, tetratricopeptide repeat domain 7A, business.industry, Hypergammaglobulinemia, Infant, Proteins, medicine.disease, Phenotype, Lymphoproliferative Disorders, 3. Good health, [SDV] Life Sciences [q-bio], Tetratricopeptide, 030104 developmental biology, medicine.anatomical_structure, Chronic Disease, mutant's cell phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, lcsh:RC581-607, 030215 immunology
Abstract

International audience; Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we report the clinical, biological and molecular features of a patient born from consanguineous parents, presenting with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO). Genetic screening revealed the novel c.974G>A (p.R325Q) mutation in homozygosity in the TTC7A gene. The patient's phenotype differs significantly from that previously associated with TTC7A deficiency in humans. It becomes closer to the one reported in the ttc7a-deficient mice that invariably develop a proliferative lymphoid and myeloid disorder. Functional studies showed that the extreme variability in the clinical phenotype couldn't be explained by the cellular phenotype. Indeed, the patient's TTC7A mutation, as well as the murine-ttc7 mutant, have the same functional impact on protein expression, DNA instability and chromatin compaction, as the other mutations that lead to classical TTC7A-associated phenotypes. Co-inheritance of genetic variants may also contribute to the unique nature of the patient's phenotype. The present case report shows that the clinical spectrum of TTC7A deficiency is much broader than previously suspected. Our findings should alert the physicians to consider screening of TTC7A mutations in patients with lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction.

Published
2019

10. Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Author

Fernando E. Sepulveda, Geneviève de Saint Basile, Patrick Nitschke, Stéphane Blanche, Maxime Battistella, David Michonneau, Nada Jabado, Shriya Deshmukh, David Mitchell, Christine Bole-Feysot, Janie Charlebois, Bénédicte Neven, Hamid Nikbakht, Mikko Taipale, Paul G Ekert, Christopher McCormack, William D. Foulkes, Leonie G. Mikael, Alexandrine Garrigue, Dzana Dervovic, Nancy Hamel, Andrea Bajic, Simon Gravel, Despina Moshous, Sharon Abish, Frank Sicheri, Rachel Conyers, Van-Hung Nguyen, Frédéric Guerin, Susan Kelso, Sylvie Fraitag, H. Miles Prince, Jean-Sebastien Diana, Rola Dali, Marianne Besnard, Jonathan Pratt, Elvis Terci Valera, Dong-Anh Khuong-Quang, Catherine Thieblemont, Alain Fischer, Tenzin Gayden, Jacek Majewski, Brigitte Bader-Meunier, Daniel Schramek, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Children’s Cancer Center, The Royal Children’s Hospital and Murdoch Children’s Research Institute, Parkville, Victoria, Australia, Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Genetics [Toronto], University of Toronto, Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada, Canadian Centre for Computational Genomics, Montreal, Canada, Division of Experimental Medicine [Montréal, QC, Canada] (Department of Medicine), McGill University Health Center [Montreal] (MUHC), Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada, Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Dermatology, St. Vincent’s Hospital, Fitzroy, Victoria, Australia, Department of Oncology [Melbourne, Australie], Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Neonatology, Centre Hospitalier de Polynésie Française, Papeete, French Polynesia, Service d'immuno-hématologie pédiatrique [CHU Necker], epartment of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Laboratoire d'anatomie pathologique [CHU Necker], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University

Subjects
0301 basic medicine, Adult, Male, Panniculitis, Adolescent, T cell, [SDV]Life Sciences [q-bio], Biology, HAVCR2, Lymphoma, T-Cell, Lymphohistiocytosis, Hemophagocytic, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immune system, Germline mutation, Subcutaneous Panniculitis-Like T-Cell Lymphoma, Exome Sequencing, Genetics, medicine, T-cell lymphoma, Humans, Genetic Predisposition to Disease, Child, Hepatitis A Virus Cellular Receptor 2, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Hemophagocytic lymphohistiocytosis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, Infant, Middle Aged, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female
Abstract

Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH–SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH–SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.

Published
2018

11. RevGel-seq: instrument-free single-cell RNA sequencing using a reversible hydrogel for cell-specific barcoding

Author

Jun Komatsu, Alba Cico, Raya Poncin, Maël Le Bohec, Jörg Morf, Stanislav Lipin, Antoine Graindorge, Hélène Eckert, Azadeh Saffarian, Léa Cathaly, Frédéric Guérin, Sara Majello, Damien Ulveling, Anaïs Vayaboury, Nicolas Fernandez, Dilyana Dimitrova, Xavier Bussell, Yannick Fourne, Pierre Chaumat, Barbara André, Elodie Baldivia, Ulysse Godet, Mathieu Guinin, Vivien Moretto, Joy Ismail, Olivier Caille, Natacha Roblot, Carine Beaupère, Alexandrine Liboz, Ghislaine Guillemain, Bertrand Blondeau, Pierre Walrafen, and Stuart Edelstein

Subjects
Medicine, Science
Abstract

Abstract Progress in sample preparation for scRNA-seq is reported based on RevGel-seq, a reversible-hydrogel technology optimized for samples of fresh cells. Complexes of one cell paired with one barcoded bead are stabilized by a chemical linker and dispersed in a hydrogel in the liquid state. Upon gelation on ice the complexes are immobilized and physically separated without requiring nanowells or droplets. Cell lysis is triggered by detergent diffusion, and RNA molecules are captured on the adjacent barcoded beads for further processing with reverse transcription and preparation for cDNA sequencing. As a proof of concept, analysis of PBMC using RevGel-seq achieves results similar to microfluidic-based technologies when using the same original sample and the same data analysis software. In addition, a clinically relevant application of RevGel-seq is presented for pancreatic islet cells. Furthermore, characterizations carried out on cardiomyocytes demonstrate that the hydrogel technology readily accommodates very large cells. Standard analyses are in the 10,000-input cell range with the current gelation device, in order to satisfy common requirements for single-cell research. A convenient stopping point after two hours has been established by freezing at the cell lysis step, with full preservation of gene expression profiles. Overall, our results show that RevGel-seq represents an accessible and efficient instrument-free alternative, enabling flexibility in terms of experimental design and timing of sample processing, while providing broad coverage of cell types.

Published
2023
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12. Author Correction: Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Author

Catherine Thieblemont, Janie Charlebois, Daniel Schramek, Jean-Sebastien Diana, Tenzin Gayden, Van-Hung Nguyen, Patrick Nitschke, Rachel Conyers, Nancy Hamel, Frédéric Guerin, Christine Bole-Feysot, Sylvie Fraitag, William D. Foulkes, Frank Sicheri, Leonie G. Mikael, Sharon Abish, Hamid Nikbakht, Rola Dali, Stéphane Blanche, Fernando E. Sepulveda, Geneviève de Saint Basile, Alain Fischer, Marianne Besnard, Christopher McCormack, Andrea Bajic, Susan Kelso, Jacek Majewski, H. Miles Prince, Simon Gravel, David Michonneau, Nada Jabado, Shriya Deshmukh, Brigitte Bader-Meunier, Maxime Battistella, Bénédicte Neven, Jonathan Pratt, Dong-Anh Khuong-Quang, Elvis Terci Valera, Dzana Dervovic, Paul G Ekert, Alexandrine Garrigue, Despina Moshous, David Mitchell, and Mikko Taipale

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.anatomical_structure, T cell, Genetics, Cancer research, medicine, Biology, HAVCR2, Panniculitis, medicine.disease, Germline
Abstract

In the version of this article originally published, the main-text sentence “In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor” misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper.

Published
2018

13. Corrigendum: Diel, seasonal, and inter-annual variation in carbon dioxide effluxes from lakes and reservoirs (2023 Environ. Res. Lett. 18 034046)

Author

Malgorzata Golub, Nikaan Koupaei-Abyazani, Timo Vesala, Ivan Mammarella, Anne Ojala, Gil Bohrer, Gesa A Weyhenmeyer, Peter D Blanken, Werner Eugster, Franziska Koebsch, Jiquan Chen, Kevin Czajkowski, Chandrashekhar Deshmukh, Frederic Guérin, Jouni Heiskanen, Elyn Humphreys, Anders Jonsson, Jan Karlsson, George Kling, Xuhui Lee, Heping Liu, Annalea Lohila, Erik Lundin, Tim Morin, Eva Podgrajsek, Maria Provenzale, Anna Rutgersson, Torsten Sachs, Erik Sahlée, Dominique Serça, Changliang Shao, Christopher Spence, Ian B Strachan, Wei Xiao, and Ankur R Desai

Subjects
Environmental technology. Sanitary engineering, TD1-1066, Environmental sciences, GE1-350, Science, Physics, QC1-999
Published
2023
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14. Diel, seasonal, and inter-annual variation in carbon dioxide effluxes from lakes and reservoirs

Author

Malgorzata Golub, Nikaan Koupaei-Abyazani, Timo Vesala, Ivan Mammarella, Anne Ojala, Gil Bohrer, Gesa A Weyhenmeyer, Peter D Blanken, Werner Eugster, Franziska Koebsch, Jiquan Chen, Kevin Czajkowski, Chandrashekhar Deshmukh, Frederic Guérin, Jouni Heiskanen, Elyn Humphreys, Anders Jonsson, Jan Karlsson, George Kling, Xuhui Lee, Heping Liu, Annalea Lohila, Erik Lundin, Tim Morin, Eva Podgrajsek, Maria Provenzale, Anna Rutgersson, Torsten Sachs, Erik Sahlée, Dominique Serça, Changliang Shao, Christopher Spence, Ian B Strachan, Wei Xiao, and Ankur R Desai

Subjects
eddy covariance, freshwater systems, lakes, reservoirs, carbon flux, synthesis, Environmental technology. Sanitary engineering, TD1-1066, Environmental sciences, GE1-350, Science, Physics, QC1-999
Abstract

Accounting for temporal changes in carbon dioxide (CO _2 ) effluxes from freshwaters remains a challenge for global and regional carbon budgets. Here, we synthesize 171 site-months of flux measurements of CO _2 based on the eddy covariance method from 13 lakes and reservoirs in the Northern Hemisphere, and quantify dynamics at multiple temporal scales. We found pronounced sub-annual variability in CO _2 flux at all sites. By accounting for diel variation, only 11% of site-months were net daily sinks of CO _2 . Annual CO _2 emissions had an average of 25% (range 3%–58%) interannual variation. Similar to studies on streams, nighttime emissions regularly exceeded daytime emissions. Biophysical regulations of CO _2 flux variability were delineated through mutual information analysis. Sample analysis of CO _2 fluxes indicate the importance of continuous measurements. Better characterization of short- and long-term variability is necessary to understand and improve detection of temporal changes of CO _2 fluxes in response to natural and anthropogenic drivers. Our results indicate that existing global lake carbon budgets relying primarily on daytime measurements yield underestimates of net emissions.

Published
2023
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15. Massive colonization of protein-coding exons by selfish genetic elements in Paramecium germline genomes.

Author

Diamantis Sellis, Frédéric Guérin, Olivier Arnaiz, Walker Pett, Emmanuelle Lerat, Nicole Boggetto, Sascha Krenek, Thomas Berendonk, Arnaud Couloux, Jean-Marc Aury, Karine Labadie, Sophie Malinsky, Simran Bhullar, Eric Meyer, Linda Sperling, Laurent Duret, and Sandra Duharcourt

Subjects
Biology (General), QH301-705.5
Abstract

Ciliates are unicellular eukaryotes with both a germline genome and a somatic genome in the same cytoplasm. The somatic macronucleus (MAC), responsible for gene expression, is not sexually transmitted but develops from a copy of the germline micronucleus (MIC) at each sexual generation. In the MIC genome of Paramecium tetraurelia, genes are interrupted by tens of thousands of unique intervening sequences called internal eliminated sequences (IESs), which have to be precisely excised during the development of the new MAC to restore functional genes. To understand the evolutionary origin of this peculiar genomic architecture, we sequenced the MIC genomes of 9 Paramecium species (from approximately 100 Mb in Paramecium aurelia species to >1.5 Gb in Paramecium caudatum). We detected several waves of IES gains, both in ancestral and in more recent lineages. While the vast majority of IESs are single copy in present-day genomes, we identified several families of mobile IESs, including nonautonomous elements acquired via horizontal transfer, which generated tens to thousands of new copies. These observations provide the first direct evidence that transposable elements can account for the massive proliferation of IESs in Paramecium. The comparison of IESs of different evolutionary ages indicates that, over time, IESs shorten and diverge rapidly in sequence while they acquire features that allow them to be more efficiently excised. We nevertheless identified rare cases of IESs that are under strong purifying selection across the aurelia clade. The cases examined contain or overlap cellular genes that are inactivated by excision during development, suggesting conserved regulatory mechanisms. Similar to the evolution of introns in eukaryotes, the evolution of Paramecium IESs highlights the major role played by selfish genetic elements in shaping the complexity of genome architecture and gene expression.

Published
2021
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16. Flow cytometry sorting of nuclei enables the first global characterization of Paramecium germline DNA and transposable elements

Author

Frédéric Guérin, Olivier Arnaiz, Nicole Boggetto, Cyril Denby Wilkes, Eric Meyer, Linda Sperling, and Sandra Duharcourt

Subjects
Flow cytometry, Non-LTR retrotransposons, ITm DNA transposons, Programmed DNA elimination, High throughput sequencing, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background DNA elimination is developmentally programmed in a wide variety of eukaryotes, including unicellular ciliates, and leads to the generation of distinct germline and somatic genomes. The ciliate Paramecium tetraurelia harbors two types of nuclei with different functions and genome structures. The transcriptionally inactive micronucleus contains the complete germline genome, while the somatic macronucleus contains a reduced genome streamlined for gene expression. During development of the somatic macronucleus, the germline genome undergoes massive and reproducible DNA elimination events. Availability of both the somatic and germline genomes is essential to examine the genome changes that occur during programmed DNA elimination and ultimately decipher the mechanisms underlying the specific removal of germline-limited sequences. Results We developed a novel experimental approach that uses flow cell imaging and flow cytometry to sort subpopulations of nuclei to high purity. We sorted vegetative micronuclei and macronuclei during development of P. tetraurelia. We validated the method by flow cell imaging and by high throughput DNA sequencing. Our work establishes the proof of principle that developing somatic macronuclei can be sorted from a complex biological sample to high purity based on their size, shape and DNA content. This method enabled us to sequence, for the first time, the germline DNA from pure micronuclei and to identify novel transposable elements. Sequencing the germline DNA confirms that the Pgm domesticated transposase is required for the excision of all ~45,000 Internal Eliminated Sequences. Comparison of the germline DNA and unrearranged DNA obtained from PGM-silenced cells reveals that the latter does not provide a faithful representation of the germline genome. Conclusions We developed a flow cytometry-based method to purify P. tetraurelia nuclei to high purity and provided quality control with flow cell imaging and high throughput DNA sequencing. We identified 61 germline transposable elements including the first Paramecium retrotransposons. This approach paves the way to sequence the germline genomes of P. aurelia sibling species for future comparative genomic studies.

Published
2017
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17. Residues essential for Panton-Valentine leukocidin S component binding to its cell receptor suggest both plasticity and adaptability in its interaction surface.

Author

Benoit-Joseph Laventie, Frédéric Guérin, Lionel Mourey, Mira Y Tawk, Emmanuel Jover, Laurent Maveyraud, and Gilles Prévost

Subjects
Medicine, Science
Abstract

Panton-Valentine leukocidin (PVL), a bicomponent staphylococcal leukotoxin, is involved in the poor prognosis of necrotizing pneumonia. The present study aimed to elucidate the binding mechanism of PVL and in particular its cell-binding domain. The class S component of PVL, LukS-PV, is known to ensure cell targeting and exhibits the highest affinity for the neutrophil membrane (Kd∼10(-10) M) compared to the class F component of PVL, LukF-PV (Kd∼10(-9) M). Alanine scanning mutagenesis was used to identify the residues involved in LukS-PV binding to the neutrophil surface. Nineteen single alanine mutations were performed in the rim domain previously described as implicated in cell membrane interactions. Positions were chosen in order to replace polar or exposed charged residues and according to conservation between leukotoxin class S components. Characterization studies enabled to identify a cluster of residues essential for LukS-PV binding, localized on two loops of the rim domain. The mutations R73A, Y184A, T244A, H245A and Y250A led to dramatically reduced binding affinities for both human leukocytes and undifferentiated U937 cells expressing the C5a receptor. The three-dimensional structure of five of the mutants was determined using X-ray crystallography. Structure analysis identified residues Y184 and Y250 as crucial in providing structural flexibility in the receptor-binding domain of LukS-PV.

Published
2014
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