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Saha D, Pramanik A, Freville A, Siddiqui AA, Pal U, Banerjee C, Nag S, Debsharma S, Pramanik S, Mazumder S, Maiti NC, Datta S, van Ooij C, Bandyopadhyay U. Structure-function analysis of nucleotide housekeeping protein HAM1 from human malaria parasite Plasmodium falciparum. FEBS J 2024; 291:4349-4371. [PMID: 39003571 DOI: 10.1111/febs.17216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 03/29/2024] [Accepted: 06/20/2024] [Indexed: 07/15/2024]
Abstract
Non-canonical nucleotides, generated as oxidative metabolic by-products, significantly threaten the genome integrity of Plasmodium falciparum and thereby, their survival, owing to their mutagenic effects. PfHAM1, an evolutionarily conserved inosine/xanthosine triphosphate pyrophosphohydrolase, maintains nucleotide homeostasis in the malaria parasite by removing non-canonical nucleotides, although structure-function intricacies are hitherto poorly reported. Here, we report the X-ray crystal structure of PfHAM1, which revealed a homodimeric structure, additionally validated by size-exclusion chromatography-multi-angle light scattering analysis. The two monomeric units in the dimer were aligned in a parallel fashion, and critical residues associated with substrate and metal binding were identified, wherein a notable structural difference was observed in the β-sheet main frame compared to human inosine triphosphate pyrophosphatase. PfHAM1 exhibited Mg++-dependent pyrophosphohydrolase activity and the highest binding affinity to dITP compared to other non-canonical nucleotides as measured by isothermal titration calorimetry. Modifying the pfham1 genomic locus followed by live-cell imaging of expressed mNeonGreen-tagged PfHAM1 demonstrated its ubiquitous presence in the cytoplasm across erythrocytic stages with greater expression in trophozoites and schizonts. Interestingly, CRISPR-Cas9/DiCre recombinase-guided pfham1-null P. falciparum survived in culture under standard growth conditions, indicating its assistive role in non-canonical nucleotide clearance during intra-erythrocytic stages. This is the first comprehensive structural and functional report of PfHAM1, an atypical nucleotide-cleansing enzyme in P. falciparum.
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Affiliation(s)
- Debanjan Saha
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Atanu Pramanik
- Division of Structural Biology & Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Aline Freville
- Department of Infection Biology, London School of Hygiene & Tropical Medicine, UK
| | - Asim Azhar Siddiqui
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Uttam Pal
- Division of Structural Biology & Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Chinmoy Banerjee
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Shiladitya Nag
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Subhashis Debsharma
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Saikat Pramanik
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Somnath Mazumder
- Department of Zoology, Raja Peary Mohan College, Uttarpara, India
| | - Nakul C Maiti
- Division of Structural Biology & Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Saumen Datta
- Division of Structural Biology & Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Christiaan van Ooij
- Department of Infection Biology, London School of Hygiene & Tropical Medicine, UK
| | - Uday Bandyopadhyay
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
- Department of Biological Sciences, Bose Institute, Kolkata, India
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Zendehdel R, Hahad O, Panjali Z. Human epithelial lung cell toxicity assessment of collected graphite particles from an iron casting industry (in vitro study). INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2024; 34:3126-3135. [PMID: 38146704 DOI: 10.1080/09603123.2023.2298248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/18/2023] [Indexed: 12/27/2023]
Abstract
Workers in the iron casting industries are exposed to various chemicals, especially graphite in furnace process. This study aims to investigate the toxic effects of graphite particles on human lung cells. Particle characteristics were confirmed by electron microscope and light scattering. Cell viability and oxidative stress markers were measured. The expression of oxidative repair genes, namely OGG1, MTH1, and ITPA, was evaluated. The average particle size was determined to be 172.1 ± 11.96 nm. The median inhibition concentration (IC50) of graphite particles was 46.75 µg/mL. Notably, 25 and 50 µg/mL concentrations resulted in significant GSH depletion and MDA production. The high concentration of graphite particles (200 µg/mL) led to OGG1 suppression and increased MTH1 expression. Based on these findings, graphite exposure may induce toxicity in human lung cells by increasing oxidative stress. Further research is necessary to fully understand the mechanisms underlying graphite toxicity.
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Affiliation(s)
- Rezvan Zendehdel
- Department of Occupational Health and Safety, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Omar Hahad
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany
| | - Zahra Panjali
- Department of Occupational Health and Safety, Faculty of Health Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Burgis NE, VanWormer K, Robbins D, Smith J. An ITPA Enzyme with Improved Substrate Selectivity. Protein J 2024; 43:62-71. [PMID: 38066288 PMCID: PMC10901923 DOI: 10.1007/s10930-023-10162-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2023] [Indexed: 02/29/2024]
Abstract
Recent clinical data have identified infant patients with lethal ITPA deficiencies. ITPA is known to modulate ITP concentrations in cells and has a critical function in neural development which is not understood. Polymorphism of the ITPA gene affects outcomes for both ribavirin and thiopurine based therapies and nearly one third of the human population is thought to harbor ITPA polymorphism. In a previous site-directed mutagenesis alanine screen of the ITPA substrate selectivity pocket, we identified the ITPA mutant, E22A, as a gain-of function mutant with enhanced ITP hydrolysis activity. Here we report a rational enzyme engineering experiment to investigate the biochemical properties of position 22 ITPA mutants and find that the E22D ITPA has two- and four-fold improved substrate selectivity for ITP over the canonical purine triphosphates ATP and GTP, respectively, while maintaining biological activity. The novel E22D ITPA should be considered as a platform for further development of ITPA therapies.
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Affiliation(s)
- Nicholas E Burgis
- Department of Chemistry, Biochemistry & Physics, Eastern Washington University, Cheney, WA, 99004, USA.
| | - Kandise VanWormer
- Department of Chemistry, Biochemistry & Physics, Eastern Washington University, Cheney, WA, 99004, USA
| | - Devin Robbins
- Department of Chemistry, Biochemistry & Physics, Eastern Washington University, Cheney, WA, 99004, USA
| | - Jonathan Smith
- Department of Chemistry, Biochemistry & Physics, Eastern Washington University, Cheney, WA, 99004, USA
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Wang X, Liu Y. Offense and Defense in Granulomatous Inflammation Disease. Front Cell Infect Microbiol 2022; 12:797749. [PMID: 35846773 PMCID: PMC9277142 DOI: 10.3389/fcimb.2022.797749] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Granulomatous inflammation (GI) diseases are a group of chronic inflammation disorders characterized by focal collections of multinucleated giant cells, epithelioid cells and macrophages, with or without necrosis. GI diseases are closely related to microbes, especially virulent intracellular bacterial infections are important factors in the progression of these diseases. They employ a range of strategies to survive the stresses imposed upon them and persist in host cells, becoming the initiator of the fighting. Microbe-host communication is essential to maintain functions of a healthy host, so defense capacity of hosts is another influence factor, which is thought to combine to determine the result of the fighting. With the development of gene research technology, many human genetic loci were identified to be involved in GI diseases susceptibility, providing more insights into and knowledge about GI diseases. The current review aims to provide an update on the most recent progress in the identification and characterization of bacteria in GI diseases in a variety of organ systems and clinical conditions, and examine the invasion and escape mechanisms of pathogens that have been demonstrated in previous studies, we also review the existing data on the predictive factors of the host, mainly on genetic findings. These strategies may improve our understanding of the mechanisms underlying GI diseases, and open new avenues for the study of the associated conditions in the future.
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Affiliation(s)
- Xinwen Wang
- Shaanxi Clinical Research Center for Oral Diseases, National Clinical Research Center for Oral Diseases, State Key Laboratory of Military Stomatology, Department of Oral Medicine, School of Stomatology, The Fourth Military Medical University, Xi’an, China
| | - Yuan Liu
- Shaanxi International Joint Research Center for Oral Diseases, State Key Laboratory of Military Stomatology, Department of Histology and Pathology, School of Stomatology, The Fourth Military Medical University, Xi’an, China
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5
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Scala M, Wortmann SB, Kaya N, Stellingwerff MD, Pistorio A, Glamuzina E, van Karnebeek CD, Skrypnyk C, Iwanicka‐Pronicka K, Piekutowska‐Abramczuk D, Ciara E, Tort F, Sheidley B, Poduri A, Jayakar P, Jayakar A, Upadia J, Walano N, Haack TB, Prokisch H, Aldhalaan H, Karimiani EG, Yildiz Y, Ceylan AC, Santiago‐Sim T, Dameron A, Yang H, Toosi MB, Ashrafzadeh F, Akhondian J, Imannezhad S, Mirzadeh HS, Maqbool S, Farid A, Al‐Muhaizea MA, Alshwameen MO, Aldowsari L, Alsagob M, Alyousef A, AlMass R, AlHargan A, Alwadei AH, AlRasheed MM, Colak D, Alqudairy H, Khan S, Lines MA, García Cazorla MÁ, Ribes A, Morava E, Bibi F, Haider S, Ferla MP, Taylor JC, Alsaif HS, Firdous A, Hashem M, Shashkin C, Koneev K, Kaiyrzhanov R, Efthymiou S, Genomics QS, Schmitt‐Mechelke T, Ziegler A, Issa MY, Elbendary HM, Striano P, Alkuraya FS, Zaki MS, Gleeson JG, Barakat TS, Bierau J, van der Knaap MS, Maroofian R, Houlden H. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency. Hum Mutat 2022; 43:403-419. [PMID: 34989426 PMCID: PMC9152572 DOI: 10.1002/humu.24326] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 12/20/2021] [Accepted: 12/29/2021] [Indexed: 12/12/2022]
Abstract
Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.
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Affiliation(s)
- Marcello Scala
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child HealthUniversità Degli Studi di GenovaGenoaItaly
- Pediatric Neurology and Muscular Diseases UnitIRCCS Istituto Giannina GasliniGenoaItaly
- UCL Queen Square Institute of NeurologyUniversity College LondonLondonUK
| | - Saskia B. Wortmann
- Amalia Children's HospitalRadboud University NijmegenNijmegenThe Netherlands
- University Children's HospitalParacelsus Medical UniversitySalzburgAustria
| | - Namik Kaya
- Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
- Department of Translational Genomics, Center for Genomics MedicineKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Menno D. Stellingwerff
- Department of Child Neurology, Emma Children's Hospital, Amsterdam Leukodystrophy Center, Amsterdam University Medical CentersVrije Universiteit and Amsterdam NeuroscienceAmsterdamThe Netherlands
| | - Angela Pistorio
- Clinical Epidemiology and Biostatistics UnitIRCCS Istituto Giannina GasliniGenoaItaly
| | - Emma Glamuzina
- Adult and Paediatric National Metabolic ServiceStarship Children's HospitalAucklandNew Zealand
| | - Clara D. van Karnebeek
- Departments of Pediatrics and Clinical GeneticsAcademic Medical CentreAmsterdamThe Netherlands
| | - Cristina Skrypnyk
- Department of Molecular Medicine, Al‐Jawhara Centre for Molecular MedicineArabian Gulf UniversityManamaKingdom of Bahrain
| | - Katarzyna Iwanicka‐Pronicka
- Department of Medical GeneticsThe Children's Memorial Health InstituteWarsawPoland
- Department of Audiology and PhoniatricsThe Children's Memorial Health InstituteWarsawPoland
| | | | - Elżbieta Ciara
- Department of Medical GeneticsThe Children's Memorial Health InstituteWarsawPoland
| | - Frederic Tort
- Secció d'Errors Congènits del Metabolisme‐IBC, Servei de Bioquímica iGenètica MolecularHospital Clínic, IDIBAPS, CIBERERBarcelonaSpain
| | - Beth Sheidley
- Department of NeurologyF.M. Kirby Neurobiology Center, Boston Children's HospitalBostonMassachusettesUSA
- Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics ProgramBoston Children's HospitalBostonMassachusettesUSA
| | - Annapurna Poduri
- Department of NeurologyF.M. Kirby Neurobiology Center, Boston Children's HospitalBostonMassachusettesUSA
- Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics ProgramBoston Children's HospitalBostonMassachusettesUSA
- Department of NeurologyHarvard Medical SchoolBostonMassachusettesUSA
| | | | | | - Jariya Upadia
- Tulane University School of MedicineNew OrleansLouisianaUSA
| | | | - Tobias B. Haack
- Institute of Medical Genetics and Applied GenomicsUniversity of TübingenTübingenGermany
| | - Holger Prokisch
- Institute of Human GeneticsTechnische Universität MünchenMunichGermany
- Institute of Human GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
| | - Hesham Aldhalaan
- Department of NeurosciencesKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Ehsan G. Karimiani
- Department of Medical GeneticsNext Generation Genetic PolyclinicMashhadIran
- Molecular and Clinical Sciences InstituteSt. George's University of London, Cranmer TerraceLondonUK
- Innovative Medical Research CenterIslamic Azad University, Mashhad BranchMashhadIran
| | - Yilmaz Yildiz
- Pediatric Metabolic Diseases ClinicDr. Sami Ulus Training and Research Hospital for Maternity and ChildrenAnkaraTurkey
| | - Ahmet C. Ceylan
- Department of Medical GeneticsAnkara City HospitalAnkaraTurkey
| | | | | | | | - Mehran B. Toosi
- Pediatric Neurology Department, Ghaem HospitalMashhad University of Medical SciencesMashhadIran
| | - Farah Ashrafzadeh
- Department of PediatricsMashhad University of Medical SciencesMashhadIran
| | - Javad Akhondian
- Pediatric Neurology Department, Ghaem HospitalMashhad University of Medical SciencesMashhadIran
| | - Shima Imannezhad
- Department of Pediatric DiseasesMashhad University of Medical SciencesMashhadIran
| | - Hanieh S. Mirzadeh
- Department of Pediatric DiseasesMashhad University of Medical SciencesMashhadIran
| | - Shazia Maqbool
- Development and Behavioral Pediatrics DepartmentInstitute of Child Health and The Children HospitalLahorePakistan
| | - Aisha Farid
- Development and Behavioral Pediatrics DepartmentInstitute of Child Health and The Children HospitalLahorePakistan
| | - Mohamed A. Al‐Muhaizea
- Department of NeurosciencesKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Meznah O. Alshwameen
- Department of NeurosciencesKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Lama Aldowsari
- Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Maysoon Alsagob
- Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Ashwaq Alyousef
- Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Rawan AlMass
- Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Aljouhra AlHargan
- Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Ali H. Alwadei
- Neurosciences DepartmentKing Fahad Medical CityRiyadhSaudi Arabia
| | - Maha M. AlRasheed
- Department of Clinical PharmacyKing Saud UniversityRiyadhSaudi Arabia
| | - Dilek Colak
- Department of Biostatistics, Epidemiology and Scientific ComputingKFSHRCRiyadhKingdom of Saudi Arabia
| | - Hanan Alqudairy
- Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Sameena Khan
- Department of NeurosciencesKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Matthew A. Lines
- Medical Genetics, Department of PediatricsAlberta Children's HospitalCalgaryCanada
| | | | - Antonia Ribes
- Secció d'Errors Congènits del Metabolisme‐IBC, Servei de Bioquímica iGenètica MolecularHospital Clínic, IDIBAPS, CIBERERBarcelonaSpain
| | - Eva Morava
- Department of Clinical Genomics, Laboratory of Medicine and PathologyCenter for Individualized Medicine, Mayo ClinicRochesterMinnesotaUSA
| | - Farah Bibi
- Institute of Biochemistry and BiotechnologyPir Mehar Ali Shah Arid Agriculture UniversityRawalpindiPakistan
| | - Shahzad Haider
- Izzat Ali Shah HospitalLalarukh Wah CanttRawalpindiPakistan
| | - Matteo P. Ferla
- NIHR Oxford BRC Genomic Medicine, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Jenny C. Taylor
- NIHR Oxford BRC Genomic Medicine, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Hessa S. Alsaif
- Department of Translational Genomics, Center for Genomics MedicineKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Abdulwahab Firdous
- Department of Translational Genomics, Center for Genomics MedicineKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Mais Hashem
- Department of Translational Genomics, Center for Genomics MedicineKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
| | - Chingiz Shashkin
- International University of Postgraduate EducationAlmatyKazakhstan
| | - Kairgali Koneev
- Department of Neurology and NeurosurgeryAsfendiyarov Kazakh National Medical UniversityAlmatyKazakhstan
| | - Rauan Kaiyrzhanov
- UCL Queen Square Institute of NeurologyUniversity College LondonLondonUK
| | | | | | | | - Andreas Ziegler
- Zentrum für Kinder und Jugendmedizin Heidelberg, Sektion Neuropädiatrie und StoffwechselmedizinUniversitätsklinikum HeidelbergHeidelbergGermany
| | - Mahmoud Y. Issa
- Clinical Genetics Department, Human Genetics and Genome Research DivisionNational Research CentreCairoEgypt
| | - Hasnaa M. Elbendary
- Clinical Genetics Department, Human Genetics and Genome Research DivisionNational Research CentreCairoEgypt
| | - Pasquale Striano
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child HealthUniversità Degli Studi di GenovaGenoaItaly
- Pediatric Neurology and Muscular Diseases UnitIRCCS Istituto Giannina GasliniGenoaItaly
| | - Fowzan S. Alkuraya
- Department of Translational Genomics, Center for Genomics MedicineKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
- Department of Anatomy and Cell BiologyAlfaisal UniversityRiyadhSaudi Arabia
| | - Maha S. Zaki
- Clinical Genetics Department, Human Genetics and Genome Research DivisionNational Research CentreCairoEgypt
| | - Joseph G. Gleeson
- Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical InstituteUniversity of CaliforniaSan DiegoCaliforniaUSA
| | - Tahsin Stefan Barakat
- Department of Clinical Genetics, Erasmus MCUniversity Medical CenterRotterdamThe Netherlands
| | - Jorgen Bierau
- Laboratory of Biochemical Genetics, Department of Clinical GeneticsMaastricht University HospitalMaastrichtThe Netherlands
| | - Marjo S. van der Knaap
- Department of Child Neurology, Emma Children's Hospital, Amsterdam Leukodystrophy Center, Amsterdam University Medical CentersVrije Universiteit and Amsterdam NeuroscienceAmsterdamThe Netherlands
- Department of Functional Genomics, Center for Neurogenomics and Cognitive ResearchVU UniversityAmsterdamThe Netherlands
| | - Reza Maroofian
- UCL Queen Square Institute of NeurologyUniversity College LondonLondonUK
| | - Henry Houlden
- UCL Queen Square Institute of NeurologyUniversity College LondonLondonUK
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Zamzami MA. Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies. Cells 2022; 11:384. [PMID: 35159194 PMCID: PMC8833965 DOI: 10.3390/cells11030384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 11/16/2022] Open
Abstract
Inosine triphosphate pyrophosphatase (ITPase) is an enzyme encoded by the ITPA gene and functions to prevent the incorporation of noncanonical purine nucleotides into DNA and RNA. Specifically, the ITPase catalyzed the hydrolysis of (deoxy) nucleoside triphosphates ((d) NTPs) into the corresponding nucleoside monophosphate with the concomitant release of pyrophosphate. Recently, thiopurine drug metabolites such as azathioprine have been included in the lists of ITPase substrates. Interestingly, inosine or xanthosine triphosphate (ITP/XTP) and their deoxy analogs, deoxy inosine or xanthosine triphosphate (dITP/dXTP), are products of important biological reactions such as deamination that take place within the cellular compartments. However, the incorporation of ITP/XTP, dITP/dXTP, or the genetic deficiency or polymorphism of the ITPA gene have been implicated in many human diseases, including infantile epileptic encephalopathy, early onset of tuberculosis, and the responsiveness of patients to cancer therapy. This review provides an up-to-date report on the ITPase enzyme, including information regarding its discovery, analysis, and cellular localization, its implication in human diseases including cancer, and its therapeutic potential, amongst others.
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Affiliation(s)
- Mazin A. Zamzami
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Centre of Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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7
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Li M, Hu Y, Zhao B, Chen L, Huang H, Huai C, Zhang X, Zhang J, Zhou W, Shen L, Zhen Q, Li B, Wang W, He L, Qin S. A next generation sequencing combined genome-wide association study identifies novel tuberculosis susceptibility loci in Chinese population. Genomics 2021; 113:2377-2384. [PMID: 34052317 DOI: 10.1016/j.ygeno.2021.05.035] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 11/17/2020] [Accepted: 05/26/2021] [Indexed: 02/07/2023]
Abstract
The genetic factors of tuberculosis (TB) susceptibility have been widely recognized. Here we performed a two-stage study in 616 TB patients and 709 healthy controls to systematically identify the genetic markers of TB susceptibility. In the discovery stage, we identified 93 single nucleotide polymorphisms (SNPs) and 3 human leucocyte antigen (HLA) class II alleles that had potential associations with TB susceptibility. In the validation stage, we confirmed that 6 nominally significant SNPs, including 2 novel missense variants at RAB17 and DCTN4 (odds ratio (OR) = 1.40, P = 4.98 × 10-3 and OR = 2.30, P = 3.17 × 10-2 respectively), were associated with the predisposition to TB. Moreover, our study found that HLA-II allele DQA1*05:05 (P = 0.0011, OR = 1.44, 95%CI = 1.15-1.77) was a TB susceptibility locus for the first time. This study comprehensively investigated the genetic variants that were associated with TB susceptibility and provided insight into the tuberculosis pathogenesis.
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Affiliation(s)
- Mo Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yi Hu
- Department of Epidemiology, China and Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai 200032, China
| | - Baihui Zhao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Luan Chen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Hailiang Huang
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Cong Huai
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Xiaoqing Zhang
- Department of Pharmacy, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Jinghong Zhang
- Center for Tuberculosis Control and Prevention, Shandong Provincial Chest Hospital, Jinan, Shandong 250013, China
| | - Wei Zhou
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Lu Shen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Qi Zhen
- Department of Dermatology, No. 1 Hospital and Key Laboratory of Dermatology (Ministry of Education), Anhui Medical University, Hefei, Anhui 230032, China
| | - Bao Li
- Department of Dermatology, No. 1 Hospital and Key Laboratory of Dermatology (Ministry of Education), Anhui Medical University, Hefei, Anhui 230032, China
| | - Wenjun Wang
- Department of Dermatology, No. 1 Hospital and Key Laboratory of Dermatology (Ministry of Education), Anhui Medical University, Hefei, Anhui 230032, China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510182, China
| | - Shengying Qin
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Collaborative Innovation Center, Jining Medical University, Jining, Shandong 272067, China.
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8
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Franca R, Zudeh G, Pagarin S, Rabusin M, Lucafò M, Stocco G, Decorti G. Pharmacogenetics of thiopurines. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:256-270. [PMID: 35582727 PMCID: PMC8992634 DOI: 10.20517/cdr.2019.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/16/2019] [Accepted: 03/21/2019] [Indexed: 11/12/2022]
Abstract
Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia (ALL) always include thiopurines. Specific approaches vary in terms of drugs, dosages and combinations. Such therapeutic schemes, including risk-adapted intensity, have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90% in developed countries. Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes. Nevertheless, daily oral thiopurines remain the backbone maintenance or continuation therapy. Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available. Other genes of interest, such as ITPA and PACSIN2, have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols. In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.
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Affiliation(s)
- Raffaella Franca
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34127, Italy
| | - Giulia Zudeh
- PhD Course in Reproductive and Developmental Sciences, University of Trieste, Trieste 34127, Italy
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Sofia Pagarin
- Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy
| | - Marco Rabusin
- Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy
| | - Marianna Lucafò
- Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy
- Experimental and Clinical Pharmacology Unit, Centro di riferimento oncologico, I.R.C.C.S., Aviano 33081, Italy
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Giuliana Decorti
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34127, Italy
- Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy
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9
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Tang NLS, Wang X, Chang KC, Chan CY, Szeto NWS, Huang D, Wu J, Lui GCY, Leung CC, Hui M. Genetic susceptibility to Tuberculosis: Interaction between HLA-DQA1 and age of onset. INFECTION GENETICS AND EVOLUTION 2018; 68:98-104. [PMID: 30553063 DOI: 10.1016/j.meegid.2018.12.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/10/2018] [Accepted: 12/10/2018] [Indexed: 12/17/2022]
Abstract
Several genome-wide association studies (GWAS) identified new single nucleotide polymorphisms (SNPs) with susceptibility to Tuberculosis (TB). However, many of them were not replicated across ethnic groups. The cause of this phenomenon of genetic heterogeneity is uncertain. Here, we attempted to replicate and evaluate the mechanism that causes genetic heterogeneity in several putative TB predisposition loci found by previous GWAS, including chromosome 18q, ASAP1, DUSP14, and HLA-DQA1. A Chinese cohort of 1200 TB patients and 1280 population controls were genotyped. The results showed that genetic predisposition to TB might operate in an age-specific manner. While no significant association was found in the whole samples, a SNP of HLA-DQA1, rs9272785, showed suggestive association within the young-onset TB subgroup (onset at 20-40 years of age, N = 396). The results provide support for the hypothesis that there are different pathogenesis mechanisms causing clinical TB disease in different age groups, and that genetics probably play a substantial role only in young-onset TB.
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Affiliation(s)
- Nelson Leung-Sang Tang
- Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, and KIZ-CUHK Joint Laboratory of Bio-resources and Molecular Research of Common Diseases, The Chinese University of Hong Kong, Hong Kong, China.
| | - Xingyan Wang
- Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, and KIZ-CUHK Joint Laboratory of Bio-resources and Molecular Research of Common Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Kwok Chiu Chang
- Tuberculosis and Chest Service, Centre for Health Protection, Department of Health, Hong Kong, China
| | - Chiu-Yeung Chan
- Department of Microbiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Natalie Wing-Sum Szeto
- Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, and KIZ-CUHK Joint Laboratory of Bio-resources and Molecular Research of Common Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Dan Huang
- Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, and KIZ-CUHK Joint Laboratory of Bio-resources and Molecular Research of Common Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Junyi Wu
- Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, and KIZ-CUHK Joint Laboratory of Bio-resources and Molecular Research of Common Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Grace C Y Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi Chiu Leung
- Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Mamie Hui
- Department of Microbiology, The Chinese University of Hong Kong, Hong Kong, China
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10
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Dallmann-Sauer M, Correa-Macedo W, Schurr E. Human genetics of mycobacterial disease. Mamm Genome 2018; 29:523-538. [PMID: 30116885 PMCID: PMC6132723 DOI: 10.1007/s00335-018-9765-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 07/23/2018] [Indexed: 12/18/2022]
Abstract
Mycobacterial diseases are caused by members of the genus Mycobacterium, acid-fast bacteria characterized by the presence of mycolic acids within their cell walls. Claiming almost 2 million lives every year, tuberculosis (TB) is the most common mycobacterial disease and is caused by infection with M. tuberculosis and, in rare cases, by M. bovis or M. africanum. The second and third most common mycobacterial diseases are leprosy and buruli ulcer (BU), respectively. Both diseases affect the skin and can lead to permanent sequelae and deformities. Leprosy is caused by the uncultivable M. leprae while the etiological agent of BU is the environmental bacterium M. ulcerans. After exposure to these mycobacterial species, a majority of individuals will not progress to clinical disease and, among those who do, inter-individual variability in disease manifestation and outcome can be observed. Susceptibility to mycobacterial diseases carries a human genetic component and intense efforts have been applied over the past decades to decipher the exact nature of the genetic factors controlling disease susceptibility. While for BU this search was mostly conducted on the basis of candidate genes association studies, genome-wide approaches have been widely applied for TB and leprosy. In this review, we summarize some of the findings achieved by genome-wide linkage, association and transcriptome analyses in TB disease and leprosy and the recent genetic findings for BU susceptibility.
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Affiliation(s)
- Monica Dallmann-Sauer
- Program in Infectious Diseases and Immunity in Global Health, Research Institute, McGill University Health Centre, Montreal, QC, Canada.,The McGill International TB Centre, McGill University, Montreal, QC, Canada.,Departments of Human Genetics and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Wilian Correa-Macedo
- Program in Infectious Diseases and Immunity in Global Health, Research Institute, McGill University Health Centre, Montreal, QC, Canada.,The McGill International TB Centre, McGill University, Montreal, QC, Canada.,Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Erwin Schurr
- Program in Infectious Diseases and Immunity in Global Health, Research Institute, McGill University Health Centre, Montreal, QC, Canada. .,The McGill International TB Centre, McGill University, Montreal, QC, Canada. .,Departments of Human Genetics and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada. .,Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, QC, Canada.
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11
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Kinnear C, Hoal EG, Schurz H, van Helden PD, Möller M. The role of human host genetics in tuberculosis resistance. Expert Rev Respir Med 2017; 11:721-737. [PMID: 28703045 DOI: 10.1080/17476348.2017.1354700] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Tuberculosis (TB) remains a public health problem: the latest estimate of new incident cases per year is a staggering 10.4 million. Despite this overwhelming number, the majority of the immunocompetent population can control infection with Mycobacterium tuberculosis. The human genome underlies the immune response and contributes to the outcome of TB infection. Areas covered: Investigations of TB resistance in the general population have closely mirrored those of other infectious diseases and initially involved epidemiological observations. Linkage and association studies, including studies of VDR, SLC11A1 and HLA-DRB1 followed. Genome-wide association studies of common variants, not necessarily sufficient for disease, became possible after technological advancements. Other approaches involved the identification of those individuals with rare disease-causing mutations that strongly predispose to TB, epistasis and the role of ethnicity in disease. Despite these efforts, infection outcome, on an individual basis, cannot yet be predicted. Expert commentary: The early identification of future disease progressors is necessary to stem the TB epidemic. Human genetics may contribute to this endeavour and could in future suggest pathways to target for disease prevention. This will however require concerted efforts to establish large, well-phenotyped cohorts from different ethnicities, improved genomic resources and a better understanding of the human genome architecture.
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Affiliation(s)
- Craig Kinnear
- a SAMRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences , Stellenbosch University , Cape Town , South Africa
| | - Eileen G Hoal
- a SAMRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences , Stellenbosch University , Cape Town , South Africa
| | - Haiko Schurz
- a SAMRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences , Stellenbosch University , Cape Town , South Africa
| | - Paul D van Helden
- a SAMRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences , Stellenbosch University , Cape Town , South Africa
| | - Marlo Möller
- a SAMRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences , Stellenbosch University , Cape Town , South Africa
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12
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Garaeva AF, Babushkina NP, Rudko AA, Goncharova IA, Bragina EY, Freidin MB. Differential genetic background of primary and secondary tuberculosis in Russians. Meta Gene 2017. [DOI: 10.1016/j.mgene.2016.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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13
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Burgis NE. A disease spectrum for ITPA variation: advances in biochemical and clinical research. J Biomed Sci 2016; 23:73. [PMID: 27770805 PMCID: PMC5075207 DOI: 10.1186/s12929-016-0291-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 10/19/2016] [Indexed: 12/15/2022] Open
Abstract
Human ITPase (encoded by the ITPA gene) is a protective enzyme which acts to exclude noncanonical (deoxy)nucleoside triphosphates ((d)NTPs) such as (deoxy)inosine 5′-triphosphate ((d)ITP), from (d)NTP pools. Until the last few years, the importance of ITPase in human health and disease has been enigmatic. In 2009, an article was published demonstrating that ITPase deficiency in mice is lethal. All homozygous null offspring died before weaning as a result of cardiomyopathy due to a defect in the maintenance of quality ATP pools. More recently, a whole exome sequencing project revealed that very rare, severe human ITPA mutation results in early infantile encephalopathy and death. It has been estimated that nearly one third of the human population has an ITPA status which is associated with decreased ITPase activity. ITPA status has been linked to altered outcomes for patients undergoing thiopurine or ribavirin therapy. Thiopurine therapy can be toxic for patients with ITPA polymorphism, however, ITPA polymorphism is associated with improved outcomes for patients undergoing ribavirin treatment. ITPA polymorphism has also been linked to early-onset tuberculosis susceptibility. These data suggest a spectrum of ITPA-related disease exists in human populations. Potentially, ITPA status may affect a large number of patient outcomes, suggesting that modulation of ITPase activity is an important emerging avenue for reducing the number of negative outcomes for ITPA-related disease. Recent biochemical studies have aimed to provide rationale for clinical observations, better understand substrate selectivity and provide a platform for modulation of ITPase activity.
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Affiliation(s)
- Nicholas E Burgis
- Department of Chemistry and Biochemistry, Eastern Washington University, 226 Science Building, Cheney, WA, 99004, USA.
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14
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Yoneshima Y, Abolhassani N, Iyama T, Sakumi K, Shiomi N, Mori M, Shiomi T, Noda T, Tsuchimoto D, Nakabeppu Y. Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells. Sci Rep 2016; 6:32849. [PMID: 27618981 PMCID: PMC5020429 DOI: 10.1038/srep32849] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 08/16/2016] [Indexed: 12/30/2022] Open
Abstract
Deoxyinosine (dI) occurs in DNA either by oxidative deamination of a previously incorporated deoxyadenosine residue or by misincorporation of deoxyinosine triphosphate (dITP) from the nucleotide pool during replication. To exclude dITP from the pool, mammals possess specific hydrolysing enzymes, such as inosine triphosphatase (ITPA). Previous studies have shown that deficiency in ITPA results in cell growth suppression and DNA instability. To explore the mechanisms of these phenotypes, we analysed ITPA-deficient human and mouse cells. We found that both growth suppression and accumulation of single-strand breaks in nuclear DNA of ITPA-deficient cells depended on MLH1/PMS2. The cell growth suppression of ITPA-deficient cells also depended on p53, but not on MPG, ENDOV or MSH2. ITPA deficiency significantly increased the levels of p53 protein and p21 mRNA/protein, a well-known target of p53, in an MLH1-dependent manner. Furthermore, MLH1 may also contribute to cell growth arrest by increasing the basal level of p53 activity.
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Affiliation(s)
- Yasuto Yoneshima
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8581, Japan
| | - Nona Abolhassani
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan
| | - Teruaki Iyama
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan
| | - Kunihiko Sakumi
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan
- Research Center for Nucleotide Pool, Kyushu University, Fukuoka 812-8581, Japan
| | - Naoko Shiomi
- National Institute of Radiological Sciences, Chiba 263-8555, Japan
| | - Masahiko Mori
- National Institute of Radiological Sciences, Chiba 263-8555, Japan
| | - Tadahiro Shiomi
- National Institute of Radiological Sciences, Chiba 263-8555, Japan
| | - Tetsuo Noda
- Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Daisuke Tsuchimoto
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan
- Research Center for Nucleotide Pool, Kyushu University, Fukuoka 812-8581, Japan
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan
- Research Center for Nucleotide Pool, Kyushu University, Fukuoka 812-8581, Japan
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