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8 results on '"MESH : Sequence Deletion"'

1. Evidence for the negative regulation of phytase gene expression in Streptomyces lividans and Streptomyces coelicolor

Author

Boukhris, Ines, Dulermo, Thierry, Chouayekh, Hichem, Virolle, Marie-Joëlle, Centre de Biotechnologie de Sfax ( CBS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Centre de Biotechnologie de Sfax (CBS), Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : Operon, [SDV]Life Sciences [q-bio], MESH: Base Sequence, MESH : Promoter Regions, Genetic, MESH : Glucuronidase, MESH: Glucuronidase, MESH : Bacterial Proteins, MESH: 6-Phytase, MESH : Streptomyces coelicolor, Promoter Regions, Genetic, MESH: Bacterial Proteins, Soil Microbiology, Glucuronidase, Sequence Deletion, 6-Phytase, MESH: Gene Expression Regulation, Bacterial, MESH : Protein Binding, MESH: Sequence Deletion, Negative, Protein Binding, MESH : Gene Expression Regulation, Bacterial, MESH: Operon, Phytic Acid, MESH : Soil Microbiology, MESH: Streptomyces lividans, Streptomyces coelicolor, Beta-glucuronidase reporter gene, Bacterial Proteins, PHO box, PhoR, PhoP, Operon, MESH: Promoter Regions, Genetic, MESH: Protein Binding, MESH: Phytic Acid, Repetitive Sequences, Nucleic Acid, MESH : Streptomyces lividans, MESH: Repetitive Sequences, Nucleic Acid, Base Sequence, [ SDV ] Life Sciences [q-bio], MESH : 6-Phytase, MESH : Sequence Deletion, Gene Expression Regulation, Bacterial, MESH: Streptomyces coelicolor, MESH : Repetitive Sequences, Nucleic Acid, MESH : Phytic Acid, MESH: Soil Microbiology, Streptomyces lividans, MESH : Base Sequence, Streptomyces phytase, Positive regulation, Phosphate limitation
Abstract

International audience; Sco7697, a gene encoding a phytase, enzyme able to degrade phytate (myo-inositol 1,2,3,4,5,6-hexakis phosphate), the most abundant phosphorus storing compound in plants is present in the genome of S. coelicolor, a soil born bacteria with a saprophytic lifestyle. The expression of this gene was previously shown to be induced in conditions of Pi limitation by the response regulator PhoP binding to an operator sequence, the PHO box, located upstream of the -35 promoter sequence. A close examination of the promoter region of sco7697 revealed the presence of another putative operator site, a Direct Repeat (DR), located downstream of the -10 promoter sequence. In order to determine whether this DR played a role in regulation of sco7697 expression, different variants of the phytase gene promoter region were transcriptionally fused to the ß-glucuronidase reporter gene (GUS). As expected, deletion of the PHO box led to abolition of sco7697 induction in conditions of Pi limitation. Interestingly, alteration of the DR correlated with a dramatic increase of GUS expression but only when PhoP was present. These results demonstrated that this DR is the site of strong negative regulation by an unknown repressor. The latter would impede the necessary activation of phytase expression by PhoP.

Published
2016

2. Characterization of Unique Signature Sequences in the Divergent Maternal Protein Bcl2l10

Author

Germain Gillet, Abdel Aouacheria, François Penin, Aurélie Cornut-Thibaut, Yannis Guillemin, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ganivet, Agnès, Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
MESH : Cell Line, MESH : Molecular Sequence Data, Amino Acid Motifs, MESH: Amino Acid Sequence, MESH: Base Sequence, MESH : Proto-Oncogene Proteins c-bcl-2, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: INDEL Mutation, protein sequence, MESH: Amino Acid Motifs, MESH: Protein Structure, Tertiary, 0302 clinical medicine, INDEL Mutation, Databases, Genetic, genetic polymorphism, MESH : Female, MESH: Animals, MESH: Genetic Variation, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Peptide sequence, MESH: Databases, Genetic, MESH: Evolution, Molecular, Sequence Deletion, Genetics, chemistry.chemical_classification, 0303 health sciences, MESH : Amino Acid Sequence, MESH : Sequence Alignment, apoptosis, Vertebrate, MESH: Sequence Deletion, Amino acid, Proto-Oncogene Proteins c-bcl-2, MESH: Calcium, 030220 oncology & carcinogenesis, Female, MESH : Protein Structure, Tertiary, MESH : Amino Acid Motifs, Molecular Sequence Data, MESH: Sequence Alignment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sequence alignment, Biology, Cell Line, MESH: Oocytes, Evolution, Molecular, 03 medical and health sciences, Bcl-2 family, MESH : Genetic Variation, biology.animal, evolution, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetic variation, Homologous chromosome, Animals, Humans, MESH : HeLa Cells, MESH : Evolution, Molecular, Amino Acid Sequence, MESH : Calcium, MESH : Databases, Genetic, Indel, MESH : INDEL Mutation, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, MESH : Mutagenesis, Insertional, calcium, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH : Sequence Deletion, MESH: Apoptosis, MESH : Humans, MESH : Oocytes, Genetic Variation, Protein Structure, Tertiary, MESH: Cell Line, Mutagenesis, Insertional, MESH: Mutagenesis, Insertional, MESH: Proto-Oncogene Proteins c-bcl-2, chemistry, MESH: HeLa Cells, Oocytes, MESH : Base Sequence, MESH : Animals, Sequence Alignment, MESH: Female, MESH : Apoptosis, HeLa Cells
Abstract

International audience; Insertions or deletions (indels) of amino acids residues have been recognized as an important source of genetic and structural divergence between paralogous Bcl-2 family members. However, these signature sequences have not so far been extensively investigated amongst orthologous Bcl-2 family proteins. Bcl2l10 is an antiapoptotic member of the Bcl-2 family that has evolved rapidly throughout the vertebrate lineage and which shows conserved abundant expression in eggs and oocytes. In this paper, we have unraveled two major sites of divergence between human Bcl2l10 and its vertebrate homologs. The first one provides length variation at the N-terminus (before the BH4 domain) and the second one is located between the predicted α5-α6 pore-forming helices, providing an unprecedented case in the superfamily of helix-bundled pore-forming proteins. These two particular indels were studied phylogenetically and through biochemical and cell biological techniques, including truncation and site-directed mutagenesis. While deletion of the N-terminal extension had no significant functional impact in HeLa cells, our results suggest that the human Bcl2l10 protein evolved a calcium-binding motif in its α5-α6 interhelical region by acquiring critical negatively charged residues. Considering the reliance of female eggs on calcium-dependent proteins and calcium-regulated processes and the exceptional longevity of oocytes in the primate lineage, we propose that this microstructural variation may be an adaptive feature associated with high maternal expression of this Bcl-2 family member.

Published
2011

3. Ceftazidime-hydrolysing -lactamase OXA-145 with impaired hydrolysis of penicillins in Pseudomonas aeruginosa

Author

Barbara Dehecq, Mélanie Colomb, Djalal Meziane-Cherif, Olivier Belmonte, Patrick Plésiat, Didier Hocquet, Patrice Courvalin, Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Agents antibactériens, Institut Pasteur [Paris] (IP), Agents pathogènes et inflammation - UFC (EA 4266) (API), Université de Franche-Comté (UFC), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Institut Pasteur [Paris], Agents pathogènes et inflammation - UFC (EA 4266) ( API ), Université de Franche-Comté ( UFC ), and Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE)

Subjects
MESH : Escherichia coli, MESH: Sequence Analysis, DNA, MESH: Ceftazidime, MESH : Mutant Proteins, Cephalosporin, MESH: beta-Lactamases, Ceftazidime, MESH : Ceftazidime, Polymerase Chain Reaction, MESH: Mutant Proteins, MESH : Isoelectric Point, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, polycyclic compounds, MESH : DNA, Bacterial, Pharmacology (medical), MESH : Anti-Bacterial Agents, Cloning, Molecular, MESH : Polymerase Chain Reaction, Sequence Deletion, chemistry.chemical_classification, MESH: Microbial Sensitivity Tests, 0303 health sciences, MESH: Kinetics, integumentary system, MESH: Escherichia coli, Hydrolysis, Omega loop, MESH : beta-Lactamases, MESH : Pseudomonas aeruginosa, MESH: Sequence Deletion, MESH : Mutagenesis, Site-Directed, Anti-Bacterial Agents, Amino acid, MESH: Mutagenesis, Site-Directed, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, Biochemistry, Pseudomonas aeruginosa, MESH: Pseudomonas aeruginosa, MESH : Penicillins, MESH : Kinetics, MESH: Hydrolysis, medicine.drug, DNA, Bacterial, Microbiology (medical), MESH : Cloning, Molecular, medicine.drug_class, Microbial Sensitivity Tests, Penicillins, Biology, beta-Lactamases, 03 medical and health sciences, MESH : Hydrolysis, MESH: Penicillins, MESH: Anti-Bacterial Agents, Escherichia coli, medicine, Humans, Nitrocefin, MESH: Cloning, Molecular, Isoelectric Point, Monobactams, 030304 developmental biology, Pharmacology, MESH: Humans, MESH: Isoelectric Point, 030306 microbiology, MESH : Sequence Deletion, MESH : Humans, MESH: Polymerase Chain Reaction, Sequence Analysis, DNA, biochemical phenomena, metabolism, and nutrition, MESH: DNA, Bacterial, Penicillin, Kinetics, chemistry, Mutagenesis, Site-Directed, bacteria, Mutant Proteins, MESH : Microbial Sensitivity Tests, MESH : Sequence Analysis, DNA
Abstract

International audience; OBJECTIVES: To describe a novel extended-spectrum oxacillinase, named OXA-145, differing from narrow-spectrum OXA-35 (from the OXA-10 group) by deletion of residue Leu-165. The genetic environment of bla(OXA-145) and the biochemical properties of OXA-145 are reported. We also assessed the impact of the Leu-165 deletion on the hydrolysis spectrum of the ancestor OXA-10. METHODS: Extended-spectrum β-lactamase OXA-145 was identified in the multidrug-resistant clinical Pseudomonas aeruginosa 08-056, and characterized by isoelectric focusing, PCR and DNA sequencing. Antibiotic susceptibility tests were performed by agar dilution. The resistance profiles conferred by cloned bla(OXA-10), bla(OXA-35), bla(OXA-145) and a bla(OXA-10) derivative obtained by site-directed mutagenesis were determined in Escherichia coli. Kinetic parameters of OXA-35 and OXA-145 were established after purification of His-tagged proteins. RESULTS: The sequence of OXA-145, encoded by a class 1 integron-borne gene in strain 08-056, differed from that of narrow-spectrum penicillinase OXA-35 by a single amino acid deletion (Leu-165) located in the highly conserved omega loop. Deletion of Leu-165 from OXA-35 (yielding OXA-145) or OXA-10 (the progenitor of OXA-35) extended the hydrolysis spectrum to third-generation cephalosporins and to monobactams, while reducing that for penicillins. OXA-145 showed biphasic hydrolysis curves for all the substrates tested. Its activity against nitrocefin was 10-fold higher in the presence of sodium hydrogen carbonate. CONCLUSIONS: OXA-145 is a new extended-spectrum β-lactamase from the OXA-10 group. The deletion of Leu-165 is responsible for a shift in the hydrolysis spectrum from penicillins to third-generation cephalosporins, as well as monobactams. The loss of penicillin hydrolysis was due to a non-carboxylated Lys-73.

Published
2011

4. Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma

Author

Agata Cieslak, André Baruchel, Elizabeth Macintyre, Céline Callens, Claudine Schmitt, Anne Moreau, Patrick Villarese, Arnaud Petit, Raouf Ben Abdelali, Frederic Baleydier, Veronique Minard-Colin, Etienne Lengliné, Yves Bertrand, Anne Rullier, Vahid Asnafi, 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 ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), CIC - Biotherapie - GHU Ouest APHP ( CIC-BT 502 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP], CHU Trousseau [APHP], Laboratoire d'hématologie ( ERL 8254 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -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 ), Department of Immunology, Duke University Medical Center, Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de Mathématiques et Applications ( LMA-Poitiers ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -CHU Saint Louis [APHP], Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], 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), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CIC - Biotherapie - GHU Ouest APHP (CIC-BT 502), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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)-Sorbonne Université (SU), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Mathématiques et Applications (LMA-Poitiers), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Male, Cancer Research, F-Box-WD Repeat-Containing Protein 7, MESH : F-Box Proteins, Cell Cycle Proteins, MESH : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, MESH: Calcium-Binding Proteins, MESH : Child, Preschool, medicine.disease_cause, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, MESH: Receptor, Notch1, MESH : Receptors, Antigen, T-Cell, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH : Cell Cycle Proteins, MESH : Child, MESH: Child, MESH : Calcium-Binding Proteins, MESH : Female, Receptor, Notch1, Prospective cohort study, Child, Sequence Deletion, 0303 health sciences, Mutation, MESH : Prognosis, MESH : Receptor, Notch1, MESH: Receptors, Antigen, T-Cell, MESH : Infant, MESH: Sequence Deletion, Prognosis, MESH: Infant, 3. Good health, MESH: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Female, MESH : Mutation, MESH : Apoptosis Regulatory Proteins, MESH: Mutation, Tumor suppressor gene, Adolescent, T cell, Ubiquitin-Protein Ligases, MESH : Male, Receptors, Antigen, T-Cell, MESH: F-Box Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH : Adolescent, medicine, Humans, 030304 developmental biology, MESH: Adolescent, MESH: Humans, business.industry, MESH: Apoptosis Regulatory Proteins, F-Box Proteins, MESH : Sequence Deletion, Lymphoblastic lymphoma, T-cell receptor, Calcium-Binding Proteins, MESH: Child, Preschool, MESH : Humans, Infant, medicine.disease, Minimal residual disease, MESH: Ubiquitin-Protein Ligases, MESH: Male, Clinical trial, Cancer research, MESH : Ubiquitin-Protein Ligases, business, Apoptosis Regulatory Proteins, MESH: Female
Abstract

Purpose Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/Fmut), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL. Patients and Methods Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/Fmut were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRγ deletions, which were interpreted in conjunction with TCRγ, TCRβ, and TCRδ rearrangements. Results N/Fmut were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P < .01) and overall survival (P < .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCRγ deletion (ABD) was seen in 7%, all of which were N/Fmut and identified a poor prognosis group (P = .02). On multivariate analysis of N/Fmut, TCRγ ABD, and FLASH deletion, only N/Fmut was an independent factor for good prognosis. Conclusion Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL.

Published
2012

5. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

Author

Im, Kate M., Kirchhoff, Tomas, Wang, Xianshu, Green, Todd, Chow, Clement Y., Vijai, Joseph, Korn, Joshua, Gaudet, Mia M., Fredericksen, Zachary, Pankratz, V. Shane, Guiducci, Candace, Crenshaw, Andrew, McGuffog, Lesley, Kartsonaki, Christiana, Morrison, Jonathan, Healey, Sue, Sinilnikova, Olga M., Mai, Phuong L., Greene, Mark H., Piedmonte, Marion, Rubinstein, Wendy S., Hogervorst, Frans B. L., Rookus, Matti A., Collee, Margriet J., Hoogerbrugge, Nicoline, van Asperen, Christi J., Meijers-Heijboer, Hanne E. J., van Roozendaal, Cees E., Caldes, Trinidad, Perez Segura, Pedro, Jakubowska, Anna, Lubinski, Jan, Huzarski, Tomasz, Blecharz, Pawel, Nevanlinna, Heli, Aittomaki, Kristiina, Lazaro, Conxi, Blanco, Ignacio, Barkardottir, Rosa B., Montagna, Marco, D'Andrea, Emma, Devilee, Peter, Olopade, Olufunmilayo I., Neuhausen, Susan L., Peissel, Bernard, Bonanni, Bernardo, Peterlongo, Paolo, Singer, Christian F., Rennert, Gad, Lejbkowicz, Flavio, Andrulis, Irene L., Glendon, Gord, Ozcelik, Hilmi, Toland, Amanda Ewart, Caligo, Maria Adelaide, Beattie, Mary S., Chan, Salina B., Domchek, Susan M., Nathanson, Katherine L., Rebbeck, Timothy R., Phelan, Catherine M., Narod, Steven A., John, Esther M., Hopper, John L., Buys, Saundra, Daly, Mary B., Southey, Melissa C., Terry, Mary Beth, Tung, Nadine, Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Duran, Mercedes, Weitzel, Jeffrey N., Garber, Judy, Hamann, Ute, Peock, Susan, Cook, Margaret, Oliver, Clare T., Frost, Debra, Platte, Radka, Evans, D. Gareth, Eeles, Ros, Izatt, Louise, Paterson, Joan, Brewer, Carole, Hodgson, Shirley V., Morrison, Patrick J., Porteous, Mary E., Walker, Lisa, Rogers, Mark T., Side, Lucy E., Godwin, Andrew K., Schmutzler, Rita K., Wappenschmidt, Barbara, Laitman, Yael, Meindl, Alfons, Deissler, Helmut, Varon-Mateeva, Raymonda, Preisler-Adams, Sabine, Kast, Karin, Venat-Bouvet, Laurence, Stoppa-Lyonnet, Dominique, Chenevix-Trench, Georgia, Easton, Douglas F., Klein, Robert J., Daly, Mark J., Friedman, Eitan, Dean, Michael, Clark, Andrew G., Altshuler, David M., Antoniou, Antonis C., Couch, Fergus J., Offit, Kenneth, Gomez Garcia, Encarna, Blok, Marinus, Gold, Bert, center for cancer research, Cancer inflammation, Department of Environmental Medicine, New York University School of Medicine-NYU Cancer Institute, Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Genetics [Boston], Harvard Medical School [Boston] ( HMS ), Cornell University, Department of Medical Genetics, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ), Queensland Institute of Medical Research, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Léon Bérard [Lyon], Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Department of Clinical Genetics, Erasmus University Medical Center-Family Cancer Clinic, Human Genetics, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Genetics and Pathology, Pomeranian Medical University-International Hereditary Cancer Centre, International Hereditary Cancer Center, Pomeranian Medical University, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Genetic Counselling Unit, Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Department of Oncology and Surgical Sciences, University of Padua and Istituto Oncologico Veneto IOV - IRCCS, Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Ontario Cancer Genetics Network, Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital ( MSH ), Section of Genetic Oncology, University Hospital and University of Pisa, Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, Women's College Research Institute, University of Toronto, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Institute of Biology and Molecular Genetics, Universidad de Valladolid [Valladolid] ( UVa ), Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum ( DKFZ ), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Addenbrookes Hospital, Royal Devon & Exeter Hospital, Medical Genetics Unit, University College of London [London] ( UCL ), South East of Scotland Regional Genetics Service, Western General Hospital, Oxford Regional Genetics Service, Churchill Hospital Oxford Centre for Haematology, Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Technical University of Munich ( TUM ), University Hospital Ulm, Charite berlin, Westfälische Wilhelms-Universität Münster ( WWU ), University Hospital Carl Gustav Carus, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Service de Génétique Oncologique, INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Department of Molecular Biology and Genetics, Cornell University, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-NYU Cancer Institute, Harvard Medical School [Boston] (HMS), Cornell University [New York], University of Cambridge [UK] (CAM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Universita degli Studi di Padova, Mount Sinai Hospital [Toronto, Canada] (MSH), Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Universidad de Valladolid [Valladolid] (UVa), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University College of London [London] (UCL), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Universitätsklinikum Ulm - University Hospital of Ulm, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Westfälische Wilhelms-Universität Münster (WWU), Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Klinische Genetica, Universitat de Barcelona, Internal Medicine, Pediatric Surgery, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mount Sinai Hospital (MSH), Technical University of Munich (TUM), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Human genetics, and CCA - Oncogenesis

Subjects
Linkage disequilibrium, endocrine system diseases, MESH : BRCA2 Protein, MESH : Genotype, Deafness, MESH: Base Sequence, MESH: Founder Effect, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, 0302 clinical medicine, MESH: BRCA2 Protein, MESH : Polychondritis, Relapsing, MESH : Female, Polychondritis, Relapsing, skin and connective tissue diseases, Genetics (clinical), Sequence Deletion, MESH: Heterozygote, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, Tay-Sachs disease, MESH: Sequence Deletion, Founder Effect, Ashkenazi jews, 3. Good health, MESH : Jews, MESH : Computer Simulation, 030220 oncology & carcinogenesis, MESH: Jews, Female, MESH: Polychondritis, Relapsing, Heterozygote, MESH : Heterozygote, MESH : Deafness, Genotype, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Population, MESH : Founder Effect, MESH: Deafness, MESH: Arthritis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Chromosomes, 03 medical and health sciences, SDG 3 - Good Health and Well-being, MESH: Computer Simulation, medicine, Humans, Computer Simulation, MESH : BRCA1 Protein, education, Allele frequency, MESH : Haplotypes, 030304 developmental biology, MESH: BRCA1 Protein, BRCA2 Protein, MESH: Humans, Hereditary cancer and cancer-related syndromes [ONCOL 1], Base Sequence, Arthritis, MESH : Sequence Deletion, Haplotype, MESH : Humans, MESH: Haplotypes, MESH : Arthritis, medicine.disease, Cromosomes, Haplotypes, Jews, MESH : Base Sequence, Selective sweep, MESH: Female, Founder effect
Abstract

Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

Published
2011

6. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours

Author

Camilla Pilati, Tina Izard, Charles Balabaud, Sandrine Imbeaud, Gabrielle Couchy, Paulette Bioulac-Sage, Karine Poussin, Jessica Zucman-Rossi, Mohamed Amessou, Sandra Rebouissou, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Genexpress, Génomique Fonctionnelle et Biologie Systémique pour la Santé, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Department of Cancer Biology, The Scripps Research Institute [La Jolla, San Diego], Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, ARC, LNCC, Inca, fondation de france, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), The Scripps Research Institute, Genomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -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 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -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 ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Zucman-Rossi, Jessica

Subjects
MESH: Inflammation, MESH: Signal Transduction, Somatic cell, MESH : heaptocellular carcinoma, MESH: mutation, MESH: Adenoma, Liver Cell, 0302 clinical medicine, oncogene, MESH : STAT3 Transcription Factor, Cytokine Receptor gp130, MESH : Interferons, MESH: Interferons, STAT3, Sequence Deletion, Regulation of gene expression, 0303 health sciences, Multidisciplinary, biology, MESH: STAT3 Transcription Factor, MESH: Gene Expression Regulation, Neoplastic, MESH: Sequence Deletion, Gene Expression Regulation, Neoplastic, MESH : mutation, MESH : Cytokine Receptor gp130, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.symptom, Signal Transduction, STAT3 Transcription Factor, MESH: Cell Line, Tumor, MESH : Interleukin-6, Adenoma, MESH : Gene Expression Regulation, Neoplastic, hepatocellular adenoma, MESH : gp130, heaptocellular carcinoma, Inflammation, MESH : oncogene, Article, Adenoma, Liver Cell, 03 medical and health sciences, gp130, MESH: Gene Expression Profiling, MESH : Adenoma, Liver Cell, Cell Line, Tumor, medicine, Humans, MESH: gp130, MESH : hepatocellular adenoma, 030304 developmental biology, MESH : Signal Transduction, MESH : Inflammation, MESH: Humans, Interleukin-6, MESH : Cell Line, Tumor, Gene Expression Profiling, MESH : Sequence Deletion, MESH : Gene Expression Profiling, MESH : Humans, MESH: hepatocellular adenoma, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatocellular adenoma, medicine.disease, MESH: heaptocellular carcinoma, MESH: Interleukin-6, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, MESH: Cytokine Receptor gp130, inflammation, biology.protein, Cancer research, Inflammatory Hepatocellular Adenoma, Interferons, mutation, MESH: oncogene
Abstract

International audience; Inflammatory hepatocellular adenomas are benign liver tumours defined by the presence of inflammatory infiltrates and by the increased expression of inflammatory proteins in tumour hepatocytes. Here we show a marked activation of the interleukin (IL)-6 signalling pathway in this tumour type; sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene, which encodes the signalling co-receptor gp130. Indeed, 60% of inflammatory hepatocellular adenomas harbour small in-frame deletions that target the binding site of gp130 for IL-6, and expression of four different gp130 mutants in hepatocellular cells activates signal transducer and activator of transcription 3 (STAT3) in the absence of ligand. Furthermore, analysis of hepatocellular carcinomas revealed that rare gp130 alterations are always accompanied by beta-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas fully explains activation of the acute inflammatory phase observed in tumourous hepatocytes, and suggests that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation.

Published
2009

7. The SH2 domain-containing inositol 5-phosphatase SHIP1 is recruited to the intracytoplasmic domain of human FcgammaRIIB and is mandatory for negative regulation of B cell activation

Author

Marc Daëron, Wolf H. Fridman, Georges Bismuth, Pierre Bruhns, Isabelle Isnardi, Allergologie Moléculaire et Cellulaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Immunologie Cellulaire et Clinique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunopharmacologie Moléculaire, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Detchepare, Christine, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UMR_S567 / UMR 8104 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -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 ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
MESH: Signal Transduction, Cytoplasm, MESH : Phosphoric Monoester Hydrolases, MESH: Amino Acid Sequence, Lymphocyte Activation, SH2 domain, Mice, chemistry.chemical_compound, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Immunology and Allergy, Inositol, MESH: Animals, Tyrosine, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Cells, Cultured, MESH : Receptors, IgG, Sequence Deletion, B-Lymphocytes, 0303 health sciences, MESH : Amino Acid Sequence, breakpoint cluster region, MESH: Sequence Deletion, medicine.anatomical_structure, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, MESH: Phosphoric Monoester Hydrolases, GRB2, Signal transduction, MESH : Protein Structure, Tertiary, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Signal Transduction, MESH: Cells, Cultured, MESH : Cytoplasm, MESH : Recombinant Fusion Proteins, Recombinant Fusion Proteins, Immunology, Phosphatase, Biology, MESH: Receptors, IgG, MESH : B-Lymphocytes, [ SDV.IMM.ALL ] Life Sciences [q-bio]/Immunology/Allergology, 03 medical and health sciences, MESH: B-Lymphocytes, MESH : Cells, Cultured, MESH : Mice, medicine, MESH: Recombinant Fusion Proteins, Animals, Humans, Amino Acid Sequence, MESH: Lymphocyte Activation, MESH: Mice, MESH : Lymphocyte Activation, B cell, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, MESH : Sequence Deletion, MESH: Cytoplasm, Receptors, IgG, MESH : Humans, Phosphoric Monoester Hydrolases, Protein Structure, Tertiary, chemistry, Cancer research, biology.protein, MESH : Animals, 030215 immunology
Abstract

Murine FcgammaRIIB were demonstrated to recruit SH2 domain-containing inositol 5-phosphatases (SHIP1/2), when their ITIM is tyrosyl-phosphorylated upon co-aggregation with BCR, and SHIP1 to account for FcgammaRIIB-dependent negative regulation of murine B cell activation. Although human FcgammaRIIB share the same ITIM as murine FcgammaRIIB and similarly inhibit human B cell activation, which among the four known SH2 domain-containing (tyrosine or inositol) phosphatases is/are recruited by human FcgammaRIIB is unclear. Our recent finding that, besides the ITIM, a second tyrosine-based motif is mandatory for murine FcgammaRIIB to recruit SHIP1 challenged the possibility that human FcgammaRIIB recruit this phosphatase. Human FcgammaRIIB indeed lack this motif. Using an experimental model which enabled us to compare human FcgammaRIIB and murine FcgammaRIIB under strictly controlled conditions, we show that SHIP1 is recruited to the intracytoplasmic domain of human FcgammaRIIB and inhibits the same biological responses and intracellular signals as when recruited by murine FcgammaRIIB. Identical results were observed in murine and in human B cells. We demonstrate that SHIP is necessary for human FcgammaRIIB to inhibit BCR signaling, and cannot be replaced by SHP-1 or SHP-2. Although it contains no tyrosine, the C-terminal segment of human FcgammaRIIB was as mandatory as the tyrosine-containing C-terminal segment of murine FcgammaRIIB for SHIP1 to be recruited to the ITIM. This segment, however, did not recruit the adapters Grb2/Grap which were demonstrated to stabilize the recruitment of SHIP1 to the ITIM in murine FcgammaRIIB.

Published
2006

8. Eight previously unidentified mutations found in the OA1 ocular albinism gene

Author

Josseline Kaplan, Elise Heon, Daniel F. Schorderet, Helene Mayeur, Alex V. Levin, Dominique Bonneau, Maurice Menasche, Marc Abitbol, Hélène Dollfus, Joanne Sutherland, Eedy Mezer, Dominique Marchant, Cécile Marsac, Didier Lacombe, Olivier Roche, Jean-Louis Dufier, Carolina Jaliffa, Francis L. Munier, Edith Said, Christelle Vêtu, EA no 2502 du ministère de la Recherche, de l'Enseignement Supérieur et la Technologie, Université Paris Descartes - Paris 5 (UPD5)-CERTO, Service d'ophtalmologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Jules Gonin Eye Hospital, Institut de Recherche en Ophtalmologie (IRO), Institut de Recherche en Ophtalmologie, Department of Ophthalmology and Vision Sciences, The Hospital for sick children [Toronto] (SickKids), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Department of Pediatrics and Medical Genetics, St. Luke's Hospital, Alberto Moscona Department of Ophthalmology, Rambam Health Care Campus, Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), We would like to thank Rétina France, Président Claude Foucher, Pr Jean- Louis Dufier, Dean Patrick Berche, Genespoir, Fondation pour la Recherche Médicale, Fondation de France, Lions Club de France, Fondation de L'Avenir, Association Française contre les Myopathies, ORPHANET, INSERM, CNRS, Ministère de la Recherche, de l'Enseignement Supérieur et de la Technologie, Faculté de Médecine René Descartes, Brandan's Eye Research Fund (AL) and Essilor for their support., Autard, Delphine, Université Paris Descartes - Paris 5 ( UPD5 ) -CERTO, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université d'Angers ( UA ) -CHU Angers, Institut de Recherche en Ophtalmologie ( IRO ), The Hospital for Sick Children, Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Handicaps génétiques de l'enfant ( Inserm U393 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
MESH : Point Mutation, Male, MESH : Molecular Sequence Data, genetic structures, MESH: Membrane Glycoproteins, DNA Mutational Analysis, MESH : Membrane Glycoproteins, MESH: RNA Splice Sites, MESH: Amino Acid Sequence, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, MESH: Research Support, Non-U.S. Gov't, Exon, 0302 clinical medicine, MESH : Research Support, Non-U.S. Gov't, MESH: Eye Proteins, Gene duplication, MESH : Female, Genetics(clinical), MESH: DNA Mutational Analysis, Genetics (clinical), Sequence Deletion, Genetics, 0303 health sciences, Mutation, Membrane Glycoproteins, MESH : Amino Acid Sequence, Albinism, Ocular, Amino Acid Sequence, Eye Proteins, Female, Humans, Molecular Sequence Data, Pedigree, Point Mutation, RNA Splice Sites, MESH: Sequence Deletion, 3. Good health, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [ SDV.MHEP.OS ] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Ocular albinism type 1, MESH : Mutation, MESH : RNA Splice Sites, Research Article, Ocular albinism, lcsh:Internal medicine, MESH: Mutation, lcsh:QH426-470, MESH: Pedigree, MESH : Male, MESH : DNA Mutational Analysis, Biology, 03 medical and health sciences, MESH : Eye Proteins, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, lcsh:RC31-1245, Gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Albinism, Ocular, MESH: Point Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, MESH : Albinism, Ocular, Point mutation, MESH : Sequence Deletion, Alternative splicing, MESH : Humans, medicine.disease, Molecular biology, MESH: Male, eye diseases, lcsh:Genetics, MESH : Pedigree, 030221 ophthalmology & optometry, sense organs, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female
Abstract

Background Ocular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene. Methods The ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments. Results We sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found. Conclusion The identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand.

Published
2006

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