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1. Iron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice

Author

Lionel Mercier, Alain Deroussent, Fabienne Munier, Clémentine Richard, Dominique Valteau-Couanet, Angelo Paci, Gilles Vassal, Bassim Tou, Jérôme Bouligand, Cedric Orear, Paule Opolon, Romain Kessari, Nicolas Simonnard, and Estelle Daudigeos-Dubus

Subjects
Male, Melphalan, Iron Overload, medicine.medical_treatment, Pharmaceutical Science, Biology, Pharmacology, 030226 pharmacology & pharmacy, Mice, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Pharmacokinetics, Neuroblastoma, medicine, Animals, Drug Interactions, Pharmacology (medical), cardiovascular diseases, Antineoplastic Agents, Alkylating, Busulfan, Chemotherapy, Organic Chemistry, Drug interaction, medicine.disease, Mice, Inbred C57BL, surgical procedures, operative, 030220 oncology & carcinogenesis, Toxicity, Molecular Medicine, Biotechnology, medicine.drug
Abstract

Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level.We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice.Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism.Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.

Published
2016

2. SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development

Author

Jacques Young, Corinne Metay, Jérôme Bouligand, Audrey Briand-Suleau, Blandine Esteva, Lucie Tosca, Bruno Francou, Gérard Tachdjian, Julie Sarfati, Anne Guiochon-Mantel, Sophie Brisset, Frédéric Brioude, Luigi Maione, Bassim Tou, and Michel Goossens

Subjects
Male, Olfactory system, Genetics, Kallmann syndrome, Puberty, Rehabilitation, Genetic disorder, Obstetrics and Gynecology, Semaphorin-3A, SEMA3A, Kallmann Syndrome, Biology, medicine.disease, Phenotype, Pedigree, Smell, Human puberty, Reproductive Medicine, Semaphorin, Olfactory nerve, medicine, Humans, Female, Gene Deletion
Abstract

background: Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with congenitally absent or impaired sense of smell. KS is related to defective neuronal development affecting both the migration of olfactory nerve endings and GnRH neurons. The discovery of several genetic mutations responsible for KS led to the identification of signaling pathways involved in these processes, but the mutations so far identified account for only 30% of cases of KS. Here, we attempted to identify new genes responsible for KS by using a pan-genomic approach. methods: From a cohort of 120 KS patients, we selected 48 propositi with no mutations in known KS genes. They were analyzed by comparative genomic hybridization array, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb. results: One propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion cosegregated in the propositus’ family with the KS phenotype, that was transmitted in autosomal dominant fashion and was not associated with other neurological or non-neurological clinical disorders. SEMA3A codes for semaphorin 3A, a protein that interacts with neuropilins. Mice lacking semaphorin 3A expression have been showed to have a Kallmann-like phenotype. conclusions: SEMA3A is therefore a new gene whose loss-of-function is involved in KS. These findings validate the specific role of semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.

Published
2012

3. SALL4 and NFATC2: two major actors of interstitial 20q13.2 duplication.: Genotype-phenotype relevance in 20q13.2 gain

Author

Bassim Tou, J. Bachir, Christine Francannet, Lucie Tosca, Audrey Briand-Suleau, Joris Vermeesch, Irina Giurgea, Michel Goossens, Sophie Brisset, Alexandra Benachi, Philippe Vago, Valérie Delattre, Jérôme Bouligand, Corinne Metay, P. Folliot, Anne Guiochon-Mantel, Carole Goumy, Jelena Martinovic, Gérard Tachdjian, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Plateforme de Génétique Constitutionnelle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Unité fonctionnelle de Fœtopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Modèles de Cellules Souches Malignes et Thérapeutiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Service d'Histologie, Embryologie et Cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Cytogénétique Médicale, CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA)-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Service de Gynécologie Obstétrique, Centre for Human Genetics, Grants from the French Ministry (DHOS)., Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)

Subjects
Heart Defects, Congenital, Male, Chromosomes, Human, Pair 22, Developmental Disabilities, Karyotype, dysmorphism, Biology, Craniofacial Abnormalities, Young Adult, 03 medical and health sciences, SALL4, Gene Duplication, Gene duplication, Genetics, cardiac malformation, Humans, 20q13.2 microduplication, Abnormalities, Multiple, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, In Situ Hybridization, Fluorescence, Genetics (clinical), 030304 developmental biology, Chromosome Aberrations, Comparative Genomic Hybridization, 0303 health sciences, NFATC Transcription Factors, 030305 genetics & heredity, Breakpoint, Chromosome, NFATC2, General Medicine, developmental delay, Fetal Diseases, Child, Preschool, NFATC2 Gene, Female, Chromosome 20, Abnormality, Transcription Factors
Abstract

International audience; Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed.

Published
2014

4. Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures

Author

Didier Lacombe, Bertrand Isidor, Albert David, Gaelle Thierry, Laurent Pasquier, Céline Bonnet, M. P. Quere, Caroline Rooryck, Olivier Pichon, Cédric Le Caignec, Bassim Tou, Sylvie Jaillard, Françoise Popelard, Christèle Dubourg, Elisabeth Flori, Ann-Charlotte Thuresson, Claire Beneteau, L. Duboscq-Bidot, Cecilia Soussi-Zander, Bert B.A. de Vries, Marie-Ange Delrue, Bregje W.M. van Bon, Annick Toutain, Corinne Metay, Mylène Beri, Anne Dusser, Agathe Paubel, Dorothée Cailley, Philippe Jonveaux, Benoit Arveiler, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Pédiatrie, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, Genetics and Pathology [Uppsala, Sueden] (IGP), Uppsala University, Department of Human Genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Plateforme Génétique Constitutionnelle CGH Array, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Service de neurologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique moléculaire, pharmacogénétique et hormonologie, Service de Radiologie Pédiatrique, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier Jean Monnet, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), De Villemeur, Hervé, and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, Candidate gene, Microcephaly, RNA, Untranslated, Heterogeneous-Nuclear Ribonucleoprotein U, [SDV.GEN] Life Sciences [q-bio]/Genetics, Corpus callosum, corpus callosum, Intellectual disability, FAM36A, deletion, chromosome, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Genetics, Comparative Genomic Hybridization, 0303 health sciences, 030305 genetics & heredity, Chromosomes, Human, Pair 1, intellectual disability, Child, Preschool, HNRNPU, Medical genetics, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Chromosome Deletion, 1q44, medicine.medical_specialty, seizure, Biology, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, Seizures, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Craniofacial, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Gene Expression Profiling, Facies, Infant, medicine.disease, ncRNA, Karyotyping, Mutation, Comparative genomic hybridization
Abstract

International audience; Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genes-HNRNPU and FAM36A-and one non-coding gene-NCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures. © 2012 Wiley Periodicals, Inc.

Published
2012

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