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1. Exome sequencing for diagnosis of congenital hemolytic anemia

Author

Lamisse Mansour-Hendili, Abdelrazak Aissat, Bouchra Badaoui, Mehdi Sakka, Christine Gameiro, Valérie Ortonne, Orianne Wagner-Ballon, Serge Pissard, Véronique Picard, Khaldoun Ghazal, Michel Bahuau, Corinne Guitton, Ziad Mansour, Mylène Duplan, Arnaud Petit, Nathalie Costedoat-Chalumeau, Marc Michel, Pablo Bartolucci, Stéphane Moutereau, Benoît Funalot, and Frédéric Galactéros

Subjects
Hemolysis, Red blood cell, Membrane, NGS, Anemia, Congenital, Medicine
Abstract

Abstract Background Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis. Results A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients. Conclusion The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients’ healthcare and probably has to be democratized notably for complex cases.

Published
2020
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2. Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier.

Author

Alexandre Hinzpeter, Abdel Aissat, Elvira Sondo, Catherine Costa, Nicole Arous, Christine Gameiro, Natacha Martin, Agathe Tarze, Laurence Weiss, Alix de Becdelièvre, Bruno Costes, Michel Goossens, Luis J Galietta, Emmanuelle Girodon, and Pascale Fanen

Subjects
Genetics, QH426-470
Abstract

Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies.

Published
2010
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3. Acquired Spherocytosis Due to Somatic ANK1 Mutations as a Manifestation of Clonal Hematopoiesis in Elderly Patients

Author

Lamisse Mansour‐Hendili, Edouard Flamarion, Marc Michel, Caroline Morbieu, Christine Gameiro, Ivan Sloma, Bouchra Badaoui, Luc Darnige, Marion Camard, Ariane Lunati‐Rozie, Abdelrazak Aissat, Sihem Tarfi, Chloé Friedrich, Véronique Picard, Loïc Garçon, Nasséra Abermil, Sophie Kaltenbach, Isabelle Radford‐Weiss, Olivier Kosmider, Pascale Fanen, Pablo Bartolucci, Bertrand Godeau, Frédéric Galactéros, Benoît Funalot, Hôpital Henri Mondor, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de Référence Maladies auto-immunes Systémiques Rares [CHU Pitié-Salpêtrière], Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Laboratoire d'Hématologie et d'Immunologie [CHU Henri Mondor], 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), GHU AP-HP Centre Université de Paris, Université Paris Cité (UPCité), Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Université Sorbonne Paris Cité (USPC), IMRB - GEIC2O/'Genetic and Environmental Interactions in COPD, Cystic fibrosis and Other (rare) respiratory diseases' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité des Maladies Génétiques du Globule Rouge [CHU Mondor], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
Ankyrins, Mutation, Humans, Spherocytosis, Hereditary, Hematology, Clonal Hematopoiesis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Aged, Hematopoiesis
Abstract

International audience

Published
2022
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4. <scp> VPS4A </scp> mutation in syndromic congenital hemolytic anemia without obvious signs of dyserythropoiesis

Author

Frédéric Galactéros, Catherine Garel, Arnaud Petit, Pablo Bartolucci, Benoît Funalot, Lydie Burglen, Virginie Saillour, Lamisse Mansour-Hendili, Abdelrazak Aissat, Leila Qebibo, Ariane Lunati, Christine Gameiro, Diane Doummar, Pascale Fanen, and Hélène Lapillonne

Subjects
Whole genome sequencing, medicine.diagnostic_test, business.industry, Anemia, Magnetic resonance imaging, Heterozygote advantage, Hematology, medicine.disease, Bioinformatics, Reticulocyte count, Mutation (genetic algorithm), medicine, Missense mutation, business, Congenital hemolytic anemia
Published
2021
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5. Les anémies hémolytiques constitutionnelles de causes multiples dévoilées par le séquençage haut-débit

Author

Bouchra Badaoui, Gonzalo De Luna, Stéphane Moutereau, Clara Noizat, Pablo Bartolucci, Sihem Tarfi, Lamisse Mansour-Hendili, Véronique Picard, Benoît Funalot, Stéphane Egée, Amna Jebali, Caroline Makowski, Frédéric Galactéros, Frédéric Garban, Christine Gameiro, Claire Barro, Abdelrazak Aissat, and Emmanuelle Faubert

Subjects
Biochemistry (medical), Clinical Biochemistry, Hematology
Published
2021
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6. Exome sequencing for diagnosis of congenital hemolytic anemia

Author

Abdelrazak Aissat, Marc Michel, Corinne Guitton, Michel Bahuau, Benoît Funalot, Pablo Bartolucci, Arnaud Petit, Orianne Wagner-Ballon, Stéphane Moutereau, Véronique Picard, Serge Pissard, Christine Gameiro, Ziad Mansour, Valérie Ortonne, Khaldoun Ghazal, Mylène Duplan, Lamisse Mansour-Hendili, Bouchra Badaoui, Mehdi Sakka, Frédéric Galactéros, and Nathalie Costedoat-Chalumeau

Subjects
0301 basic medicine, Hemolytic anemia, Pediatrics, medicine.medical_specialty, Anemia, lcsh:Medicine, Spherocytosis, Hereditary, Anemia, Hemolytic, Congenital, Hemolysis, Hereditary spherocytosis, 03 medical and health sciences, Congenital, 0302 clinical medicine, Genetic variation, Exome Sequencing, medicine, Humans, Pharmacology (medical), Exome, Genetics (clinical), Exome sequencing, business.industry, Research, lcsh:R, Membrane, General Medicine, medicine.disease, Human genetics, Red blood cell, 030104 developmental biology, NGS, Mutation, business, Congenital hemolytic anemia, 030215 immunology
Abstract

Background Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis. Results A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients. Conclusion The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients’ healthcare and probably has to be democratized notably for complex cases.

Published
2020

7. Comprehensive description of CFTR genotypes and ultrasound patterns in 694 cases of fetal bowel anomalies: a revised strategy

Author

Annick LeFloch, Christine Gameiro, Jean-Marie Jouannic, Emmanuelle Girodon, J.P. Martin, Rachel Médina, Corinne Alberti, Irina Giurgea, Catherine Costa, Alix de Becdelièvre, Françoise Muller, Michel Goossens, and Brigitte Boissier

Subjects
Male, medicine.medical_specialty, Cystic Fibrosis, Genotype, DNA Mutational Analysis, Cystic Fibrosis Transmembrane Conductance Regulator, Context (language use), Gene mutation, Risk Assessment, Gastroenterology, Cystic fibrosis, Ultrasonography, Prenatal, Gene Frequency, Pregnancy, Risk Factors, Internal medicine, Genetics, medicine, Echogenic Bowel, Humans, Genetics (clinical), biology, Gallbladder, Infant, Newborn, medicine.disease, Human genetics, Cystic fibrosis transmembrane conductance regulator, Phenotype, medicine.anatomical_structure, Mutation, Mutation (genetic algorithm), biology.protein, Female
Abstract

Fetal bowel anomalies may reveal cystic fibrosis (CF) and the search for CF transmembrane conductance regulator (CFTR) gene mutations is part of the diagnostic investigations in such pregnancies, according to European recommendations. We report on our 18-year experience to document comprehensive CFTR genotypes and correlations with ultrasound patterns in a series of 694 cases of fetal bowel anomalies. CFTR gene analysis was performed in a multistep process, including search for frequent mutations in the parents and subsequent in-depth search for rare mutations, depending on the context. Ultrasound patterns were correlated with the genotypes. Cases were distinguished according to whether they had been referred directly to our laboratory or after an initial testing in another laboratory. A total of 30 CF fetuses and 8 cases compatible with CFTR-related disorders were identified. CFTR rearrangements were found in 5/30 CF fetuses. 21.2% of fetuses carrying a frequent mutation had a second rare mutation, indicative of CF. The frequency of CF among fetuses with no frequent mutation was 0.43%. Correlation with ultrasound patterns revealed a significant frequency of multiple bowel anomalies in CF fetuses. The results emphasize the need to search for rearrangements in the diagnosis strategy of fetal bowel anomalies. The diagnostic value of ultrasound patterns combining hyperechogenic bowel, loop dilatation and/or non-visualized gallbladder reveals a need to revise current strategies and to offer extensive CFTR gene testing when the triad is diagnosed, even when no frequent mutation is found in the first-step analysis.

Published
2010
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8. CFTR and/or pancreatitis susceptibility genes mutations as risk factors of pancreatitis in cystic fibrosis patients?

Author

Emmanuelle Girodon, Christine Gameiro, Dominique Hubert, Daniel Dusser, Isabelle Honoré, R. Kanaan, Thierry Bienvenu, Florence Houriez, Brigitte Martinez, Pierre-Régis Burgel, Natacha Gaitch, and Jeanne Chapron

Subjects
0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Cystic Fibrosis, Genotype, Endocrinology, Diabetes and Metabolism, Cystic Fibrosis Transmembrane Conductance Regulator, Cystic fibrosis, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Prospective Studies, Age of Onset, Gene, Pancreatic duct, Hepatology, business.industry, Incidence, Pancreatic Ducts, Middle Aged, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Pancreatitis, Mutation, Acute pancreatitis, 030211 gastroenterology & hepatology, Female, Complication, business
Abstract

Background/objectives Currently, factors that promote the occurrence of pancreatitis episodes in patients affected with cystic fibrosis (CF) and pancreatic sufficiency (PS) are largely unknown. Methods Six genes involved in pancreatitis or in ion transport into the pancreatic duct were investigated by next generation sequencing in 59 adult CF-PS patients with two identified CF mutations. Data on predisposing environmental factors were also recorded. Results 19 experienced at least one episode of acute pancreatitis (AP) (AP+) and 40 patients did not (AP−). No influence of environmental factor was evidenced. No specific CFTR genotype was found predictive of pancreatitis. Patients sharing the same CFTR genotype may or may not experience AP episodes. Frequent and rare missense variants were found in 78.9% patients in group AP+ and 67.5% in group AP− but a few of them were pathogenic. Conclusions AP or recurrent AP (RAP) is a frequent complication in our series of adult CF-PS patients. The majority of mild CFTR mutations found in group AP+ were located in the first transmembrane region. No clear other genetic factor could be found predictive of AP/RAP. Further experiments in large homogenous cohorts of CF-PS patients, including whole genome sequencing, may identify genetic predisposing factors to pancreatitis.

Published
2016

9. Prognostic Value of Translocation t(11;18) in Tumoral Response of Low-Grade Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue Type to Oral Chemotherapy

Author

Christine Gameiro, Marie-Hélène Delfau-Larue, Corinne Haioun, Christiane Copie-Bergman, Michael Levy, Francois Hemery, M.T. Chaumette, Karen Leroy, Jean-Charles Delchier, Philippe Gaulard, and Antoine Charachon

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, medicine.medical_treatment, Polymerase Chain Reaction, Gastroenterology, Translocation, Genetic, Helicobacter Infections, Recurrence, Stomach Neoplasms, Internal medicine, medicine, Humans, Helicobacter, Antineoplastic Agents, Alkylating, B cell, Aged, Chemotherapy, biology, business.industry, Chromosomes, Human, Pair 11, Gastric lymphoma, Stomach, MALT lymphoma, Lymphoma, B-Cell, Marginal Zone, Middle Aged, Prognosis, medicine.disease, biology.organism_classification, Lymphoma, Treatment Outcome, medicine.anatomical_structure, Oncology, Female, Chromosomes, Human, Pair 18, business, Mucosa-associated lymphoid tissue, Follow-Up Studies
Abstract

Purpose To determine the impact of translocation t(11;18) on response to oral alkylating agents in gastric mucosa-associated lymphoid tissue lymphoma (GML). Patients and Methods Fifty-three patients with a GML were studied. Helicobacter pylori--positive patients (n = 34) received anti–H pylori treatment and H pylori–negative patients (n = 19) or patients who failed to respond to anti–H pylori treatment received oral alkylating agents. t(11;18) was detected by reverse transcription polymerase chain reaction from frozen gastric biopsies. Results t(11;18) was detected in 32% of patients. It was more prevalent in H pylori--negative as compared with H pylori--positive patients (12 of 19 v five of 34 patients; P = .0005). Among 31 H pylori–eradicated patients, t(11;18) was detected in three patients, all of whom experienced treatment failure, and it was absent in 28 patients: 21 patients (75%) were in remission and seven patients (25%) experienced treatment failure (P = .03). Among 21 patients who received an alkylating agent, t(11;18) was detected in 12 patients: five patients (42%) were in remission and seven patients (58%) experienced treatment failure. t(11;18) was absent in nine patients: eight patients (89%) were in remission and one patient (11%) experienced treatment failure by the end of treatment. Four patients in remission relapsed during follow-up (median, 7 years): they all had t(11;18). Durable remission was obtained in eight (89%) of the nine patients without t(11;18) versus one of the 12 patients (8%) with t(11;18) (P = .0003). Conclusion Presence of t(11;18) in GML is predictive of resistance to oral alkylating agents, with less than 10% of durable remission at long-term follow-up.

Published
2005
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10. Identification of a novel 5' alternative CFTR mRNA isoform in a patient with nasal polyposis and CFTR mutations

Author

Alix de Becdelièvre, Catherine Costa, F. Brémont, Pascale Fanen, Aurélie Lorot, Bruno Costes, Eric Bieth, Michel Goossens, Virginie Prulière-Escabasse, Abdel Aissat, Emmanuelle Girodon, Alexandre Hinzpeter, Christine Gameiro, Natacha Martin, 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 Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Chirurgie de la Face et du Cou, Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Centre Hospitalier Intercommunal de Créteil (CHIC), This work was supported by the French CF Foundation ' Vaincre La Mucoviscidose '., Guellaen, Georges, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Pédiatrie - Pneumologie, Allergologie, Hôpital des Enfants, and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]

Subjects
Male, DNA Mutational Analysis, Cystic Fibrosis Transmembrane Conductance Regulator, Biology, medicine.disease_cause, Cystic fibrosis, 03 medical and health sciences, Exon, 0302 clinical medicine, Nasal Polyps, Rapid amplification of cDNA ends, Gene Order, Genetics, medicine, RNA Isoforms, nasal polyposis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, CFTR, Child, Genetics (clinical), 030304 developmental biology, alternative transcripts, 0303 health sciences, Messenger RNA, Mutation, Promoter, medicine.disease, Molecular biology, Cystic fibrosis transmembrane conductance regulator, Exon skipping, Pedigree, Alternative Splicing, 030220 oncology & carcinogenesis, biology.protein, 5' Untranslated Regions, transcription regulation
Abstract

International audience; Cystic fibrosis may be revealed by nasal polyposis (NP) starting early in life. We performed cystic fibrosis transmembrane conductance regulator (CFTR) DNA and mRNA analyses in the family of a 12-year-old boy presenting with NP and a normal sweat test. Routine DNA analysis only showed the heterozygous c.2551C>T (p.Arg851*) mutation in the child and the father. mRNA analysis showed partial exon skipping due to c.2551C>T and a significant increase in total CFTR mRNA in the patient and the mother, which was attributable to the heterozygous c. -2954G>A variant in the distant promoter region, as demonstrated by in vitro luciferase assays. The 5' rapid amplification of cDNA ends analysis showed the presence of a novel transcript, where the canonical exon 1 was replaced by an alternative exon called 1a-Long. This case report could represent the first description of a CFTR-related disorder associated with the presence of a 5' alternative, probably nonfunctional transcript, similar to those of fetal origin.

Published
2014
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11. A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice

Author

Lisa Golmard, Caroline Guittard, Thierry Bienvenu, Irina Giurgea, Michel Goossens, Virginie Prulière-Escabasse, Christine Gameiro, Catherine Costa, Marie des Georges, L. Bassinet, Pascale Fanen, Abdel Aissat, Eric Bieth, André Coste, Alix de Becdelièvre, Ralph Epaud, Mireille Claustres, Bruno Costes, Emmanuelle Girodon, Alexandre Hinzpeter, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Otorhinolaryngologie et chirurgie cervico-faciale [CHU Mondor], CHU Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, 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), Département de Biopathologie, Institut Curie [Paris], Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Pneumologie [Créteil], Centre Hospitalier Intercommunal Créteil (CHIC), Biochimie et biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Est (UPE), CHU Toulouse [Toulouse], Physiopathologie des maladies génétiques d'expression pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), UMR_S855, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut Curie

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, Adolescent, Cystic Fibrosis, c.870-1113_1110delGAAT, [SDV]Life Sciences [q-bio], 1002-1113_1110delGAAT, Bioinformatics, Cystic fibrosis, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genotype, medicine, Humans, Pediatrics, Perinatology, and Child Health, RNA, Messenger, CFTR, Mutation frequency, Child, Sweat test, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, business.industry, Infant, Newborn, Heterozygote advantage, Middle Aged, medicine.disease, Phenotype, Introns, 3. Good health, CFTR mRNA, Child, Preschool, Pediatrics, Perinatology and Child Health, Mutation (genetic algorithm), RNA splicing, Mutation, Female, business, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND:The identification by CFTR mRNA studies of a new deep-intronic splicing mutation, c.870-1113_1110delGAAT, in one patient of our series with mild CF symptoms and in three CF patients of an Italian study, led us to evaluate the mutation frequency and phenotype/genotype correlations.METHODS:266 patients with CF and related disorders and having at least one undetected mutation, were tested at the gDNA level in three French reference laboratories.RESULTS:In total, the mutation was found in 13 unrelated patients (5% of those already carrying a mutation) plus 4 siblings, including one homozygote and 12 heterozygotes having a severe CF mutation. The sweat test was positive in 10/14 documented cases, the diagnosis was delayed after 20 years in 9/15 and pancreatic insufficiency was present in 5/16.CONCLUSION:c.870-1113_1110delGAAT should be considered as CF-causing with phenotype variability and overall delayed diagnosis. Its frequency highlights the potential of mRNA studies.

Published
2011
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12. Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier

Author

Alix de Becdelièvre, Catherine Costa, Agathe Tarze, Laurence Weiss, Luis J. V. Galietta, Elvira Sondo, Michel Goossens, Pascale Fanen, Natacha Martin, Christine Gameiro, Nicole Arous, Emmanuelle Girodon, Alexandre Hinzpeter, Abdel Aissat, Bruno Costes, 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), Laboratorio di Genetica Molecolare, Istituto G. Gaslini, 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), Service de Pédiatrie I, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Hinzpeter, Alexandre, Aissat, Abdel, Sondo, Elvira, Costa, Catherine, Arous, Nicole, Gameiro, Christine, Martin, Natacha, Tarze, Agathe, Weiss, Laurence, de Becdelièvre, Alix, Costes, Bruno, Goossens, Michel, Galietta, Luis J., Girodon, Emmanuelle, Fanen, Pascale, Guellaen, Georges, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10

Subjects
Male, Cancer Research, Cystic Fibrosis, DNA Mutational Analysis, Cystic Fibrosis Transmembrane Conductance Regulator, HeLa Cell, 0302 clinical medicine, HEK293 Cell, INDEL Mutation, Genetics and Genomics/Genetics of Disease, Genetics (clinical), Genetics, Genetics and Genomics/Medical Genetics, 0303 health sciences, Luminescent Protein, Genetics and Genomics/Bioinformatics, Stop codon, Pedigree, Genetics and Genomics/Gene Function, Phenotype, RNA Splice Site, 030220 oncology & carcinogenesis, RNA splicing, Female, Research Article, Human, lcsh:QH426-470, Genotype, Nonsense mutation, Mutation, Missense, Biology, Transfection, DNA Mutational Analysi, 03 medical and health sciences, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Indel, Cystic Fibrosi, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Base Sequence, Alternative splicing, Intron, Ecology, Evolution, Behavior and Systematic, lcsh:Genetics, Luminescent Proteins, Alternative Splicing, HEK293 Cells, RNA Splice Sites, HeLa Cells
Abstract

Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies., Author Summary Mild disease outcomes associated with premature termination codons can result from at least three different mechanisms, but none of these mechanisms explain the mild phenotype observed in some patients. Subtle differences in alternative transcripts have recently been reported at NAGNAG tandem acceptor motifs, which can be detected in 30% of human genes. We provide the first experimental evidence of premature termination codon removal by alternative splicing at a NAGNAG acceptor splice site. Our study emphasizes the biological significance of such alternative splicing in the context of disease-causing mutations and defines a new phenotype-modifying mechanism that buffers nonsense mutations.

Published
2010
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13. WS21.6 A novel 5′ alternative CFTR mRNA isoform may be a cause of CFTR dysfunction in a patient with nasal polyposis

Author

Natacha Martin, Alexandre Hinzpeter, A. de Becdelièvre, Christine Gameiro, F. Brémont, Eric Bieth, Bruno Costes, Abdel Aissat, Catherine Costa, Michel Goossens, E. Girodon, and Pascale Fanen

Subjects
Pulmonary and Respiratory Medicine, Gene isoform, congenital, hereditary, and neonatal diseases and abnormalities, Messenger RNA, business.industry, Pediatrics, Perinatology and Child Health, Cancer research, medicine, Pediatrics, Perinatology, and Child Health, respiratory system, medicine.disease, business, Cystic fibrosis
Published
2013
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14. A new cryptic CFTR exon in mild CF

Author

E. Girodon, L. Bassinet, Christine Gameiro, Michel Goossens, Virginie Prulière-Escabasse, Lisa Golmard, A. de Becdelièvre, and Catherine Costa

Subjects
Pulmonary and Respiratory Medicine, Exon, business.industry, Pediatrics, Perinatology and Child Health, medicine, Pediatrics, Perinatology, and Child Health, medicine.disease, business, Cystic fibrosis, Molecular biology
Published
2009
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15. Identification and characterization of three CFTR gene partial duplications

Author

A. LeFloch, Michel Goossens, J Martin, Florence Niel, J. Derelle, Catherine Costa, V. Izard, Christine Gameiro, E. Girodon, Marie Legendre, and D. Grenet

Subjects
Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, business.industry, Pediatrics, Perinatology and Child Health, Medicine, Identification (biology), Pediatrics, Perinatology, and Child Health, Computational biology, respiratory system, business, medicine.disease, Cystic fibrosis, Cftr gene
Published
2008
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16. Influence of translocation t(11;18) on response to conservative treatment of MALT gastric lymphoma (MGL)

Author

Karen Leroy, Michael J. Levy, Corinne Haioun, Christiane Copie-Bergman, Christine Gameiro, Jean-Charles Delchier, Francois Hemery, Marie-Hélène Delfau-Larue, and Philippe Gaulard

Subjects
Gastrointestinal tract, Pathology, medicine.medical_specialty, Stromal cell, Hepatology, GiST, business.industry, CD68, Gastric lymphoma, Stomach, Gastroenterology, Chromosomal translocation, medicine.disease, Staining, medicine.anatomical_structure, Medicine, business
Abstract

phage COX-2 expression was also determined. Results: All of the tumors were c-kit positive confirming the diagnosis of GIST. Eighty percent (12/15) of the tumors expressed COX-2. Expression was noted in the cytoplasm of the tumor cells. There was heterogeneity of intensity of staining between the tumors. COX-2 was expressed in both epithelioid and spindled tumors, but appeared stronger in epithelioid lesions. In mixed lesions, COX-2 was expressed to a greater extent in epithelioid areas. There was a higher degree of COX-2 expression in malignant tumors and those located in the stomach. CD68 positive cells were identified in all of the lesions and in 80% of cases, these ceils also expressed COX-2. in 2 of the 3 GISTs that were COX-2 negative, macrophages expressed COX-I Conclusions: In this study, for the first time, we have demonstrated expression of COX-2 in stromal lesions of the gastrointestinal tract. The enzyme may have a role in the proliferation of these lesions, which suggests the potential use of COX-2 inhibitors for treatment of these tumors.

Published
2003
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17. A comprehensive genotype–phenotype description of 695 cases with fetal bowel anomalies

Author

E. Girodon, Christine Gameiro, A. de Becdelièvre, J.P. Martin, A. Le Floch, Catherine Costa, Brigitte Boissier, C. Alberti-Boulmé, Michel Goossens, R. Medina, Irina Giurgea, and Jean-Marie Jouannic

Subjects
Pulmonary and Respiratory Medicine, Fetus, Pathology, medicine.medical_specialty, business.industry, Pediatrics, Perinatology and Child Health, Medicine, Pediatrics, Perinatology, and Child Health, business, medicine.disease, Cystic fibrosis, Genotype phenotype
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18. 14 Genotype-phenotype correlations of the recurrent mRNA intron 6b splicing defect, 1002-1113_1110delGAAT

Author

C. Guittard, E. Girodon, L. Bassinet, Irina Giurgea, Thierry Bienvenu, Christine Gameiro, A. de Becdelièvre, M. desGeorges, André Coste, Michel Goossens, Virginie Prulière-Escabasse, and Catherine Costa

Subjects
Genetics, Pulmonary and Respiratory Medicine, Messenger RNA, business.industry, Pediatrics, Perinatology and Child Health, RNA splicing, Intron, Medicine, Pediatrics, Perinatology, and Child Health, business, medicine.disease, Cystic fibrosis, Genotype-Phenotype Correlations
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