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1. Site- and allele-specific polycomb dysregulation in T-cell leukaemia

Author

Marta Gut, Marie Loosveld, H. Bobby Gaspar, Vahid Asnafi, Estelle Duprez, Steven J. Howe, Romain Fenouil, Ivo Gut, Sébastien Jaeger, Salima Hacein-Bey-Abina, Claude Grégoire, Bernard Malissen, Adrian J. Thrasher, Dominique Payet-Bornet, Sandrine Le Noir, Bertrand Nadel, Ester Morgado, Muhammad Ahmad Maqbool, Hervé Dombret, Lydie Pradel, Emilie Mamessier, Elizabeth Macintyre, Jean-Christophe Andrau, Aurore Touzart, Myriam Koubi, Charles Pignon, Norbert Ifrah, Jean-Marc Navarro, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance Publique - Hôpitaux de Marseille (APHM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Inserm U429 (CHU Necker - Enfants Malades [AP-HP]), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), 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)-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), Hopital Saint-Louis [AP-HP] (AP-HP), University College of London [London] (UCL), Molecular Immunology Unit, University College of London [London] (UCL)-Institute of Child Health, 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), PRES Université Nantes Angers Le Mans (UNAM), Fondation pour la Recherche Médicale (#INE2003114116), Le Conseil Général des Bouches du Rhône, le Canceropôle PACA, CALYM consortium, l’Institut National du Cancer (INCa PLBIO09), la Fondation de France (#2008001490) and institutional grants from INSERM, CNRS and AMU, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Cytokines, hématopoïèse et réponse immune (CHRI), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), University College London-Institute of Child Health, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Necker Enfants-Malades ( INEM - UM 111 (UMR 8253 / U1151) ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centro Nacional de Análisi Genómico ( CNAG ), Institut de Génomique, Commissariat à l’Energie Atomique, Centre National de Genotypage, IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), University College-Institute of Child Health, 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, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institute of Child Health-University College London, and Spinelli, Lionel

Subjects
Genome instability, [SDV]Life Sciences [q-bio], Polycomb-Group Proteins, General Physics and Astronomy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Germline, Epigenesis, Genetic, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Histones, Jurkat Cells, 0302 clinical medicine, Basic Helix-Loop-Helix Transcription Factors, Cancer epigenetics, T-Cell Acute Lymphocytic Leukemia Protein 1, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Multidisciplinary, Gene Expression Regulation, Leukemic, Nuclear Proteins, Acetylation, 3. Good health, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], Treatment Outcome, 030220 oncology & carcinogenesis, T-cell lymphoma, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Plasmids, Adult, Chromatin Immunoprecipitation, Molecular Sequence Data, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Methylation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Medical research, [SDV.CAN] Life Sciences [q-bio]/Cancer, Proto-Oncogene Proteins, Polycomb-group proteins, Humans, Epigenetics, Allele, Alleles, 030304 developmental biology, Homeodomain Proteins, Base Sequence, Genetic heterogeneity, General Chemistry, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Survival Analysis, Mutagenesis, Insertional, Genetic Loci, TAL1
Abstract

T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1+ cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1+ T-ALLs. Sequencing reveals that >20% of monoallelic TAL1+ patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5′ to TAL1. Using ‘allelic-ChIP’ and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation., TAL1 is frequently deregulated in T-cell acute lymphoblastic leukaemias, but the mechanism remains largely unclear. Here the authors show that microinsertions upstream of TAL1 cause its epigenetic reactivation, and that the mode of TAL1 activation correlates with prognosis.

Published
2015
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2. Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity

Author

Gaël Ménasché, Geneviève de Saint Basile, Françoise Le Deist, Brigitte Bader-Meunier, Laurence Le Clainche, Marc Tardieu, Isabelle Callebaut, Alain Fischer, Véronique Minard-Colin, Jérôme Feldmann, 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 ), Institut de minéralogie et de physique des milieux condensés ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IPG PARIS-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Inserm U429 (CHU Necker - Enfants Malades [AP-HP]), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-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), Ménasché, Gaël, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Pathology, [SDV]Life Sciences [q-bio], Hepatosplenomegaly, CHILDREN, Biochemistry, Severity of Illness Index, 0302 clinical medicine, Cytotoxic T cell, Missense mutation, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Membrane Glycoproteins, biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, Hematology, Familial Hemophagocytic Lymphohistiocytosis, Pancytopenia, Magnetic Resonance Imaging, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], Phenotype, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Encephalitis, Female, medicine.symptom, Pore Forming Cytotoxic Proteins, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Histiocytosis, Non-Langerhans-Cell, Immunology, Encephalopathy, Molecular Sequence Data, Mutation, Missense, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cytoplasmic Granules, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine, Humans, Amino Acid Sequence, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Hemophagocytic lymphohistiocytosis, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Perforin, Infant, C2 DOMAIN, Cell Biology, medicine.disease, Protein Structure, Tertiary, biology.protein, Leukocytes, Mononuclear, FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, C2 DOMAIN, CHILDREN, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Mutations in the perforin gene cause familial hemophagocytic lymphohistiocytosis (FHL). The first symptoms of FHL are usually intractable fever, hepatosplenomegaly, and pancytopenia. Most FHL patients subsequently develop central nervous system (CNS) manifestations due to infiltration of tissues by activated lymphocytes and macrophages. We report 2 FHL patients with an atypical phenotype characterized by isolated severe neurologic symptoms mimicking chronic encephalitis and leading to an early death. Functional and molecular analyses revealed the same novel missense mutation in the perforin gene in both patients; this mutation affected the calcium-binding domain of the protein. This missense mutation did not affect perforin maturation or expression in cytotoxic cells but impaired in vitro cytotoxic activity. Diagnosis was delayed in both patients because of the initial neurologic expression and the normal expression of perforin in circulating lymphocytes. This emphasizes the importance of early diagnosis of this atypical form of FHL, as CNS involvement causes severe, irreversible encephalopathy. This observation also raises the question of the role of some mutations in the neurologic expression of FHL.

Published
2005
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3. Rab27A and its effector MyRIP link secretory granules to F-actin and control their motion towards release sites

Author

Isabelle Fanget, Sébastien Huet, François Darchen, Christine Petit, Catherine Chapuis, Graça Raposo, Viet Samuel Tran, Sophie Cribier, Geneviève de Saint Basile, Gaël Ménasché, Aziz El-Amraoui, Claire Desnos, Jean-Sébastien Schonn, Jean-Pierre Henry, Biologie cellulaire et moléculaire de la sécrétion (BCMS), Centre National de la Recherche Scientifique (CNRS), Institut de biologie physico-chimique (IBPC), Génétique des Déficits sensoriels, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Inserm U429 (CHU Necker - Enfants Malades [AP-HP]), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Laboratoire de biologie physico-chimique des protéines membranaires (LBPC-PM (UMR_7099)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), J.-S. Schonn was supported by a fellowship from the Fondation de la Recherche Médicale, and S. Huet was supported by the Direction Générale de l’Armement. This work was supported by a grant from the Ministère de la Recherche (DRAB)., Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), J.-S. Schonn was supported by a fellowship from the Fondation de la Recherche Médicale, and S. Huet was supported by the Direction Générale de l'Armement. This work was supported by a grant from the Ministère de la Recherche (DRAB)., Chapuis, Catherine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique et physiologie cellulaire, Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Biologie cellulaire et moléculaire de la sécrétion ( BCMS ), Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), 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 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Compartimentation et dynamique cellulaires ( CDC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de biologie physico-chimique des protéines membranaires ( LBPC-PM ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut de Biologie Physico-Chimique-Centre National de la Recherche Scientifique ( CNRS )

Subjects
Chromaffin Cells, [SDV]Life Sciences [q-bio], Rab27A, MyRIP, exocytosis, actin, neuroendocrine cell, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], PC12 Cells, rab27 GTP-Binding Proteins, 0302 clinical medicine, Depsipeptides, Myosin, 0303 health sciences, Secretory Vesicle, Cell biology, Actin Cytoskeleton, Melanophilin, Thiazolidines, endocrine system, Myosin Type V, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Peptides, Cyclic, Exocytosis, Article, 03 medical and health sciences, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, RAB27, Actin, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Myosin Heavy Chains, Secretory Vesicles, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Cell Biology, Actin cytoskeleton, Bridged Bicyclo Compounds, Heterocyclic, Actins, Rats, Microscopy, Electron, Thiazoles, rab GTP-Binding Proteins, Latrunculin, Cattle, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

International audience; The GTPase Rab27A interacts with myosin-VIIa and myosin-Va via MyRIP or melanophilin and mediates melanosome binding to actin. Here we show that Rab27A and MyRIP are associated with secretory granules (SGs) in adrenal chromaffin cells and PC12 cells. Overexpression of Rab27A, GTPase-deficient Rab27A-Q78L, or MyRIP reduced secretory responses of PC12 cells. Amperometric recordings of single adrenal chromaffin cells revealed that Rab27A-Q78L and MyRIP reduced the sustained component of release. Moreover, these effects on secretion were partly suppressed by the actin-depolymerizing drug latrunculin but strengthened by jasplakinolide, which stabilizes the actin cortex. Finally, MyRIP and Rab27A-Q78L restricted the motion of SGs in the subplasmalemmal region of PC12 cells, as measured by evanescent-wave fluorescence microscopy. In contrast, the Rab27A-binding domain of MyRIP and a MyRIP construct that interacts with myosin-Va but not with actin increased the mobility of SGs. We propose that Rab27A and MyRIP link SGs to F-actin and control their motion toward release sites through the actin cortex.

Published
2003
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4. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome

Author

Gaël Ménasché, Diana W. Bianchi, NM Wulffraat, Stéphanie Certain, de Saint Basile G, Fügen Ersoy, Le Deist F, Stéphanie Dupuis, Alain Fischer, Pastural E, Jérôme Feldmann, Inserm U429 (CHU Necker - Enfants Malades [AP-HP]), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Immunology Unit [Ankara, Turkey], Hacettepe Children’s Hospital [Ankara, Turkey]-University of Hacettepe [Ankara, Turkey], Unite d'Immunologie et d'Hematologie Pediatrique (CHU Necker - Enfants Malades [AP-HP]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Immunology [Utrecht, The Netherlands], Wilhelmina Children’s Hospital [Utrecht, The Netherlands], England Medical Center [Boston, MA, USA], and Ménasché, Gaël

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Genetic Linkage, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Lymphocyte Activation, rab27 GTP-Binding Proteins, 0302 clinical medicine, Child, Cells, Cultured, 0303 health sciences, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Homozygote, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Exons, Syndrome, 3. Good health, [SDV] Life Sciences [q-bio], STX11, 030220 oncology & carcinogenesis, Child, Preschool, Chromosomal region, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Saccharomyces cerevisiae Proteins, [SDV.IMM] Life Sciences [q-bio]/Immunology, Molecular Sequence Data, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Myosins, Cytoplasmic Granules, Fungal Proteins, 03 medical and health sciences, Myosin Type I, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Genetics, medicine, Humans, UNC13D, RAB27, Griscelli syndrome, 030304 developmental biology, Cytolytic granule, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Chromosomes, Human, Pair 15, Infant, medicine.disease, Molecular biology, Introns, Griscelli syndrome type 2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Melanosome transport, rab GTP-Binding Proteins, Immunology, Mutation, Pigmentation Disorders, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, T-Lymphocytes, Cytotoxic
Abstract

International audience; Griscelli syndrome (GS, MIM 214450), a rare, autosomal recessive disorder, results in pigmentary dilution of the skin and the hair, the presence of large clumps of pigment in hair shafts and an accumulation of melanosomes in melanocytes. Most patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome (known as haemophagocytic syndrome, HS), leading to death in the absence of bone-marrow transplantation. In contrast, early in life some GS patients show a severe neurological impairment without apparent immune abnormalities. We previously mapped the GS locus to chromosome 15q21 and found a mutation in a gene (MYO5A) encoding a molecular motor in two patients. Further linkage analysis suggested a second gene associated with GS was in the same chromosomal region. Homozygosity mapping in additional families narrowed the candidate region to a 3.1-cM interval between D15S1003 and D15S962. We detected mutations in RAB27A, which lies within this interval, in 16 patients with GS. Unlike MYO5A, the GTP-binding protein RAB27A appears to be involved in the control of the immune system, as all patients with RAB27A mutations, but none with the MYO5A mutation, developed HS. In addition, RAB27A-deficient T cells exhibited reduced cytotoxicity and cytolytic granule exocytosis, whereas MYO5A-defective T cells did not. RAB27A appears to be a key effector of cytotoxic granule exocytosis, a pathway essential for immune homeostasis.

Published
2000
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5. Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1)

Author

Gaël Ménasché, Chen Hsuan Ho, Ozden Sanal, Jérôme Feldmann, Ilhan Tezcan, Fügen Ersoy, Anne Houdusse, Alain Fischer, Geneviève de Saint Basile, Ménasché, Gaël, Inserm U429 (CHU Necker - Enfants Malades [AP-HP]), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hacettepe University = Hacettepe Üniversitesi, Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from INSERM, l’Association de Recherche sur le Cancer, and l’Association Vaincre les Maladies Lysosomales., Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), and Çocuk Sağlığı ve Hastalıkları

Subjects
Male, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Myosin Type V, Mutation, Missense, [SDV.GEN] Life Sciences [q-bio]/Genetics, Research & Experimental Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Models, Biological, rab27 GTP-Binding Proteins, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Animals, Humans, Amino Acid Sequence, Adaptor Proteins, Signal Transducing, Sequence Deletion, 030304 developmental biology, Hypopigmentation, 0303 health sciences, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Melanosomes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Base Sequence, Myosin Heavy Chains, DNA, Exons, Syndrome, General Medicine, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, Pedigree, [SDV] Life Sciences [q-bio], Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, rab GTP-Binding Proteins, 030220 oncology & carcinogenesis, Mutation, Female, Carrier Proteins, Corrigendum, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Hair
Abstract

International audience; Griscelli syndrome (GS) is a rare autosomal recessive disorder that associates hypopigmentation, characterized by a silver-gray sheen of the hair and the presence of large clusters of pigment in the hair shaft, and the occurrence of either a primary neurological impairment or a severe immune disorder. Two different genetic forms, GS1 and GS2, respectively, account for the mutually exclusive neurological and immunological phenotypes. Mutations in the gene encoding the molecular motor protein Myosin Va (MyoVa) cause GS1 and the dilute mutant in mice, whereas mutations in the gene encoding the small GTPase Rab27a are responsible for GS2 and the ashen mouse model. We herein present genetic and functional evidence that a third form of GS (GS3), whose expression is restricted to the characteristic hypopigmentation of GS, results from mutation in the gene that encodes melanophilin (Mlph), the ortholog of the gene mutated in leaden mice. We also show that an identical phenotype can result from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern. This spectrum of GS conditions pinpoints the distinct molecular pathways used by melanocytes, neurons, and immune cells in secretory granule exocytosis, which in part remain to be unraveled.

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