449 results on '"Philippe, M."'
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2. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
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Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics
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Male ,DISRUPTION ,Chloride Channels/genetics ,EXCHANGER ,Mutation, Missense ,LYSOSOMAL STORAGE DISEASE ,VARIANTS ,Neurodevelopmental Disorders/genetics ,PHENOTYPE ,Cellular and Molecular Neuroscience ,All institutes and research themes of the Radboud University Medical Center ,Genes, X-Linked ,CLC CHLORIDE ,Medicine and Health Sciences ,Humans ,Molecular Biology ,MUTATION ,Biology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,CHANNELS ,LINKED MENTAL-RETARDATION ,ASSOCIATION ,GENE ,Psychiatry and Mental health ,Chemistry ,Female ,Human medicine - Abstract
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
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- 2023
3. PIGG variant pathogenicity assessment reveals characteristic features within 19 families
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Anna Lehman, Christina T. Rüsch, Angela F. Brady, Julie S. Cohen, Millan S. Patel, Rani Sachdev, Usha Kini, Elizabeth E. Palmer, Reza Maroofian, Sonal Mahida, Karen Stals, Roger L. Ladda, Yoshiko Murakami, Camille Tremblay-Laganière, Tahsin Stefan Barakat, Scott D. McLean, Fizza Akbar, Marilena Christoforou, Farah Ashrafzadeh, Melissa A. Walker, Grazia M.S. Mancini, Salman Kirmani, Kimberly Nugent, Philippe M. Campeau, Fatima Y. Ismail, Amanda Nagy, Sian Ellard, Stephanie Efthymiou, Bushra Afroze, Rebecca Macintosh, Saskia B. Wortmann, Danilo Bernardo, Rebecca Truty, Matias Wagner, Shahnaz Ibrahim, Tipu Sultan, Kristin W. Barañano, Stylianos E. Antonarakis, Yuta Maki, Thi Tuyet Mai Nguyen, Henry Houlden, Robert Steinfeld, Saadet Mercimek-Andrews, Taroh Kinoshita, Georg M. Stettner, Andrew C. Edmondson, Naila Ismayilova, Meisam Babaei, Heather M. McLaughlin, Mohammad Doosti, Ehsan Ghayoor Karimiani, and Clinical Genetics
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Autism Spectrum Disorder ,Immunoglobulin D ,Article ,Cell membrane ,chemistry.chemical_compound ,Biosynthesis ,Seizures ,Intellectual Disability ,medicine ,Humans ,Transferase ,Gene ,Genetics (clinical) ,Genetics ,chemistry.chemical_classification ,Virulence ,biology ,Membrane Proteins ,Hypotonia ,In vitro ,Pedigree ,Phosphotransferases (Alcohol Group Acceptor) ,Enzyme ,medicine.anatomical_structure ,chemistry ,biology.protein ,medicine.symptom - Abstract
Purpose Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions. Unlabelled Image
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- 2021
4. An adamantamine derivative as a drug candidate for the treatment of visceral leishmaniasis
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Joël Vacus, Daniel Gillet, Julien Barbier, Laetitia Nguyen, Valérie Pons, Sébastien Pomel, Jean-Christophe Cintrat, Philippe M. Loiseau, Sandrine Cojean, and Alain Pruvost
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0301 basic medicine ,Microbiology (medical) ,030231 tropical medicine ,Antiprotozoal Agents ,ADME Study ,Drug resistance ,Pharmacology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,medicine ,Animals ,Pharmacology (medical) ,Leishmania infantum ,ADME ,Mice, Inbred BALB C ,Miltefosine ,biology ,Chemistry ,biology.organism_classification ,030104 developmental biology ,Infectious Diseases ,Pharmaceutical Preparations ,Drug development ,Leishmaniasis, Visceral ,medicine.drug - Abstract
Background This study aimed to investigate compounds acting on the host cell machinery to impair parasite installation with the possible advantage of limiting drug resistance. The strategy therefore consisted of selecting compounds that are poorly active on the axenic parasite, but very active on the intramacrophage form of Leishmania. Objectives To identify a drug candidate from focused screening of adamantamine derivatives that can inhibit the development of Leishmania infantum in macrophages. Methods In vitro screening was performed on a library of 142 adamantamine derivatives with axenic and intramacrophage forms of L. infantum, as well as cytotoxicity assays, allowing selection of the most promising compound. Absorption, distribution, metabolism and excretion (ADME) experiments, including pharmacokinetics and microsomal stability, were performed and finally the physicochemical stability of the compound was investigated to assess its suitability for further drug development. Results VP343 was identified first in vitro, with a CC50 value of 63.7 μM and an IC50 value of 0.32 μM for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10 mg/kg/day for 5 days. In addition, the ADME data were compatible with moving this compound further through the antileishmanial drug candidate pipeline. Conclusions VP343 has the properties of a good drug candidate and merits further investigations.
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- 2021
5. Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy
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Parenti, Ilaria, Lehalle, Daphné, Nava, Caroline, Torti, Erin, Leitão, Elsa, Person, Richard, Mizuguchi, Takeshi, Matsumoto, Naomichi, Kato, Mitsuhiro, Nakamura, Kazuyuki, de Man, Stella A., Cope, Heidi, Shashi, Vandana, Friedman, Jennifer, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Muffels, Irena, van Hasselt, Peter M., Petit, Florence, Smol, Thomas, Le Guyader, Gwenaël, Bilan, Frédéric, Sorlin, Arthur, Vitobello, Antonio, Philippe, Christophe, van de Laar, Ingrid M. B. H., van Slegtenhorst, Marjon A., Campeau, Philippe M., Au, Ping Yee Billie, Nakashima, Mitsuko, Saitsu, Hirotomo, Yamamoto, Tatsuya, Nomura, Yumiko, Louie, Raymond J., Lyons, Michael J., Dobson, Amy, Plomp, Astrid S., Motazacker, M. Mahdi, Kaiser, Frank J., Timberlake, Andrew T., Fuchs, Sabine A., Depienne, Christel, Mignot, Cyril, Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Deardorff, Matthew, Dell’Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldrich, Madison P., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Huryn, Laryssa, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Karaviti, Lefkothea, Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, LaMoure, Grace L., Lanpher, Brendan C., Lanza, Ian R., Latham, Lea, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., MacDowall, John, Macnamara, Ellen F., Mac-Rae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan C., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Mosbrook-Davis, Deborah, Mulvihill, John J., Murdock, David R., Nagy, Anna, Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Power, Bradley, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Shin, Jimann, Signer, Rebecca, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Jennifer A., Sullivan, Kathleen, Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Amelia L. M., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Thurm, Audrey, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yousef, Muhammad, Zastrow, Diane B., Zein, Wadih, Zhao, Chunli, Zuchner, Stephan, Clinical Genetics, Human Genetics, ACS - Pulmonary hypertension & thrombosis, and ANS - Complex Trait Genetics
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Male ,Adolescent ,Mutation, Missense ,Medizin ,Nerve Tissue Proteins ,Biology ,Frameshift mutation ,Chromodomain ,Cohort Studies ,Young Adult ,Epilepsy ,Neurodevelopmental disorder ,Catalytic Domain ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Missense mutation ,Child ,Genetics (clinical) ,Exome sequencing ,Original Investigation ,Genes, Dominant ,DNA Helicases ,medicine.disease ,Pedigree ,Neurodevelopmental Disorders ,Child, Preschool ,Speech delay ,Female ,medicine.symptom - Abstract
Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
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- 2021
6. Drugs used for the treatment of cerebral and disseminated infections caused by free‐living amoebae
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Philippe M. Loiseau, Zineb Fechtali-Moute, Alexandre Taravaud, and Sébastien Pomel
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Drug ,030213 general clinical medicine ,media_common.quotation_subject ,Reviews ,Central Nervous System Protozoal Infections ,RM1-950 ,Balamuthia ,Review ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,Balamuthia mandrillaris ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,Medicine ,Humans ,Amebicides ,General Pharmacology, Toxicology and Pharmaceutics ,Granulomatous amoebic encephalitis ,Amoeba ,media_common ,Naegleria fowleri ,biology ,business.industry ,General Neuroscience ,Meningoencephalitis ,Acanthamoeba infection ,General Medicine ,Amebiasis ,biology.organism_classification ,medicine.disease ,Acanthamoeba ,Survival Rate ,Treatment Outcome ,Immunology ,Drug Therapy, Combination ,Therapeutics. Pharmacology ,Public aspects of medicine ,RA1-1270 ,business - Abstract
Free‐living amoebae (FLAs) are protozoa developing autonomously in diverse natural or artificial environments. The FLAs Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri represent a risk for human health as they can become pathogenic and cause severe cerebral infections, named granulomatous amoebic encephalitis (GAE), Balamuthia amoebic encephalitis (BAE), and primary amoebic meningoencephalitis (PAM), respectively. Additionally, Acanthamoeba sp. can also rarely disseminate to diverse organs, such as the skin, sinuses, or bones, and cause extracerebral disseminated acanthamebiasis (EDA). No consensus treatment has been established for cerebral FLA infections or EDA. The therapy of cerebral and disseminated FLA infections often empirically associates a large diversity of drugs, all exhibiting a high toxicity. Nevertheless, these pathologies lead to a high mortality, above 90% of the cases, even in the presence of a treatment. In the present work, a total of 474 clinical cases of FLA infections gathered from the literature allowed to determine the frequency of usage, as well as the efficacy of the main drugs and drug combinations used in the treatment of these pathologies. The efficacy of drug usage was determined based on the survival rate after drug administration. The most efficient drugs, drug combinations, and their mechanism of action were discussed in regard to the present recommendations for the treatment of GAE, EDA, BAE, and PAM. At the end, this review aims to provide a useful tool for physicians in their choice to optimize the treatment of FLA infections.
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- 2021
7. JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome
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Ange Line Bruel, Katherine A. Bosanko, Abeltje M. Polstra, Agne Liedén, Marcel M.A.M. Mannens, R. Pfundt, Frédérick A. Mallette, Britt-Marie Anderlid, Kieran B. Pechter, Louise Rafael-Croes, Madhura Bakshi, Saskia M. Maas, Dagmar Glatz, R. Frank Kooy, Natalie Lippa, Philippe M. Campeau, Yuri A. Zarate, Jade England, Mieke M. van Haelst, Megan Boothe, Kosuke Izumi, Manon van Ginkel, Vimla Aggarwal, Anna Lehman, Eline A. Verberne, Zornitza Stark, Christopher M. Richmond, Marije Meuwissen, Darryl C. De Vivo, Pankaj B. Agrawal, Shuxiang Goh, Jennifer M. Lemons, Bertrand Isidor, Ayeshah Chaudhry, Causes Study, Emma Bedoukian, Nathaniel H. Robin, David A. Koolen, Sylvia Stockler, David Rodriguez-Buritica, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Human Genetics, Graduate School, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and ACS - Pulmonary hypertension & thrombosis
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0301 basic medicine ,Heterozygote ,Haploinsufficiency ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,Exome Sequencing ,Intellectual disability ,medicine ,Humans ,Copy-number variation ,Gene ,Genetics (clinical) ,Exome sequencing ,Genetics ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,neurodevelopment ,Microarray analysis techniques ,Polycomb Repressive Complex 2 ,Chromosome ,Syndrome ,medicine.disease ,developmental delay ,Phenotype ,030104 developmental biology ,Neurodevelopmental Disorders ,intellectual disability ,Histone methyltransferase ,Human medicine ,JARID2 - Abstract
Item does not contain fulltext PURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.
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- 2021
8. Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns
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Karen Doggett, Almahdi Chakroun, Alisa K. White, Joan K. Heath, Stephen Mieruszynski, Alice Abdel Aleem, Madisen F. Lee, Cinzia Magnani, Anouk M. Olthof, Rahul N. Kanadia, Justine Rousseau, Philippe M. Campeau, and Chaim M. Roifman
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Spliceosome ,Cerebellar Ataxia ,AcademicSubjects/SCI00010 ,Primary Immunodeficiency Diseases ,Biology ,Osteochondrodysplasias ,03 medical and health sciences ,Exon ,Mice ,0302 clinical medicine ,Retinal Diseases ,Minor spliceosome ,Intellectual Disability ,RNA, Small Nuclear ,Genetics ,RNA and RNA-protein complexes ,Animals ,Humans ,Cells, Cultured ,Growth Disorders ,030304 developmental biology ,0303 health sciences ,Alternative splicing ,Intron ,RNA ,Exons ,Exon skipping ,Introns ,Nonsense Mediated mRNA Decay ,Alternative Splicing ,Polyribosomes ,RNA splicing ,Mental Retardation, X-Linked ,Microcephaly ,Spliceosomes ,Apoptosis Regulatory Proteins ,Cardiomyopathies ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Vertebrate genomes contain major (>99.5%) and minor (
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- 2021
9. In vitro antileishmanial potentialities of essential oils from Citrus limon and Pistacia lentiscus harvested in Tunisia
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Marwa Yahyaoui, Ghozlene Mekhloufi, Florence Agnely, Sandrine Cojean, Zeineb Maaroufi, Philippe M. Loiseau, and Manef Abderraba
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Citrus ,Tunisia ,030231 tropical medicine ,Antiprotozoal Agents ,Leishmaniasis, Cutaneous ,Gas Chromatography-Mass Spectrometry ,030308 mycology & parasitology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Phenols ,law ,Oils, Volatile ,medicine ,Animals ,Humans ,Plant Oils ,Leishmania major ,Amastigote ,Axenic ,Essential oil ,0303 health sciences ,Miltefosine ,General Veterinary ,biology ,Pistacia ,Traditional medicine ,food and beverages ,Leishmaniasis ,General Medicine ,biology.organism_classification ,medicine.disease ,Plant Leaves ,Infectious Diseases ,Insect Science ,Pistacia lentiscus ,Parasitology ,medicine.drug - Abstract
Leishmaniasis is a tropical parasitic disease that affects up to 12 million people worldwide. Current chemotherapies have limitations such as toxicity, high cost, and parasite resistance. This work aims to select an essential oil (EssOil) isolated from the Tunisian flora as a new antileishmanial candidate. Two plants were chosen for their antileishmanial potential: Citrus limon (Citrus) and Pistacia lentiscus (Pistacia). Each of these plants was harvested from two different sites (area 1 and area 2). Extracted EssOils were characterized using GC-MS. Their antiparasitic activity against axenic and intracellular Leishmania major amastigotes and their cytotoxicity were assessed. Citrus EssOil from area 1 displayed an interesting activity against L. major intramacrophage amastigotes with IC50 value at 4.2 ± 1.3 μg/mL. Interestingly, this activity was close to that of miltefosine. Moderate activities against intracellular amastigote were observed for Pistacia EssOil from area 1 and Citrus EssOil from area 2. However, low cytotoxicity with high selectivity index was proved only for Citrus EssOil from area 1, revealing its safety for macrophages. This study also demonstrated for the first time the antileishmanial activity of EssOil extracted from Citrus limon leaves. The EssOil interesting activity could be related to the lipophilic properties of terpenes that were shown in literature to contribute to the disruption of parasite intracellular metabolic pathways.
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- 2021
10. Placement of Biological Membrane Patches in a Nanofluidic Gap With Control Over Position and Orientation
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Francesca Ruggeri, Christian Schwemmer, Mirko Stauffer, Philippe M. Nicollier, Jacqueline Figueiredo da Silva, Patrick D. Bosshart, Kirstin Kochems, Dimitrios Fotiadis, Armin Knoll, and Heiko Wolf
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Mechanics of Materials ,Mechanical Engineering ,570 Life sciences ,biology ,610 Medicine & health - Abstract
Purple membranes from the archaeon Halobacterium salinarum consist of 2D crystals of the light-driven proton pump bacteriorhodopsin, which convert photons into a proton gradient across the cell membrane. This functional feature and the structural rigidity make them appealing candidates for integration into biomimetic devices. To this end, and in order to carry out their function, purple membranes must be positioned in the correct orientation at the position of interest. Precise placement and control over the orientation of nanoscale objects still constitutes a formidable challenge. Here, it is shown that isolated purple membrane patches can be transported and positioned at predefined locations in nanofluidic confinement, with control over their orientation at the target sites. The transport is achieved through a rocking Brownian motor scheme, while the controlled deposition of the membranes is realized by engineering the surface potential of a fluid-filled nanofluidic slit. This controlled manipulation of purple membrane patches outlines a new pathway toward the integration of biological or other delicate supramolecular structures into top–down-fabricated patterns, for the assembly of nanoscale hybrid devices that serve as a light-driven source of (chemical) energy.
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- 2022
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11. De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy
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Philippe M. Campeau, Gabrielle Lemire, Smrithi Salian, Thomas Garcia, Stylianos E. Antonarakis, Sophie Ehresmann, Seth I. Berger, Justine Rousseau, Sylviane Hanquinet, Armand Bottani, Xiang-Jiao Yang, Jacques Côté, Ann C.M. Smith, Jonathan Humbert, Jennifer Heeley, Rami Alasiri, Erin Beaver, and Periklis Makrythanasis
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Adult ,Male ,Heterozygote ,Adolescent ,DNA Repair ,Mutation, Missense ,ddc:616.0757 ,Lysine Acetyltransferase 5 ,Chromatin remodeling ,Chromodomain ,Histones ,Histone H4 ,03 medical and health sciences ,0302 clinical medicine ,Cerebellar Diseases ,Intellectual Disability ,Report ,Genetics ,Humans ,ddc:576.5 ,Abnormalities, Multiple ,Epigenetics ,KAT5 ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Epilepsy ,biology ,Histone acetyltransferase ,Chromatin Assembly and Disassembly ,Chromatin ,Histone ,Child, Preschool ,biology.protein ,Female ,Cerebellar atrophy ,Atrophy ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery - Abstract
KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.
- Published
- 2020
12. Early infantile epileptic encephalopathy due to biallelic pathogenic variants in <scp> PIGQ </scp> : Report of seven new subjects and review of the literature
- Author
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Rebecca C. Spillmann, Nissan V. Baratang, Kym M. Boycott, Karen W. Gripp, Taila Hartley, Anik St-Denis, Philippe M. Campeau, Kristin D. Kernohan, Erik A. Eklund, Jessica L. Zambonin, Loren D M Pena, Michael T. Geraghty, Andrew C. Edmondson, Jacek Majewski, Hugh J. McMillan, Allan Bayat, Miao He, Manuela Pendziwiat, Eric Bareke, Andrea Guerin, Thi Tuyet Mai Nguyen, Julie Richer, Devon L. Johnstone, and Hilde M. H. Braakman
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HYPERPHOSPHATASIA ,Male ,GLYCOSYLPHOSPHATIDYLINOSITOL ,Disease ,Immunoglobulin D ,Fatal Outcome ,0302 clinical medicine ,1ST STEP ,PIGQ ,Child ,Genetics (clinical) ,Exome sequencing ,0303 health sciences ,biology ,medicine.diagnostic_test ,rare diseases ,DEFECTS ,Transfection ,Phenotype ,3. Good health ,epileptic encephalopathy ,Child, Preschool ,Muscle Hypotonia ,Original Article ,Female ,medicine.symptom ,Spasms, Infantile ,DISORDERS ,Mutation, Missense ,Status epilepticus ,Flow cytometry ,03 medical and health sciences ,Seizures ,Exome Sequencing ,Genetics ,medicine ,Humans ,BIOSYNTHESIS ,Abnormalities, Multiple ,IGD ,Gene ,030304 developmental biology ,MUTATIONS ,business.industry ,Infant, Newborn ,Infant ,Membrane Proteins ,Original Articles ,GENE ,GPI ,Immunology ,biology.protein ,business ,exome sequencing ,030217 neurology & neurosurgery - Abstract
We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)‐anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ‐related disease and provide the first functional evidence in human cells of defective GPI‐anchoring due to pathogenic variants in PIGQ.
- Published
- 2020
13. Apoprunellelactone (APL), an antiprotozoal lactone from the stem barks of Isolona cooperi Hutch. & Dalziel (Annonaceae)
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Venance Martial Say, Philippe M. Loiseau, Pierre Champy, Faustin Aka Kabran, Laurent Evanno, Bruno Figadère, Timothée Aboua Okpekon, and Alexandre Maciuk
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chemistry.chemical_classification ,Bioassay guided fractionation ,Traditional medicine ,010405 organic chemistry ,medicine.drug_class ,Organic Chemistry ,Plant Science ,Biology ,biology.organism_classification ,01 natural sciences ,Biochemistry ,Isolona cooperi ,0104 chemical sciences ,Analytical Chemistry ,010404 medicinal & biomolecular chemistry ,chemistry ,Annonaceae ,Antiprotozoal ,medicine ,Lactone - Abstract
Bioassay guided fractionation of the stem barks of Isolona cooperi led to the isolation of a new lactone, apoprunellelactone (APL, 1), and two known compounds, 5-[1-hydroxyhexyl]-2H-furan-2-one (2) and oleic acid (3). Their structures were elucidated by spectral analysis including MS, UV, IR, 1D and 2D-NMR spectroscopy. Evaluated for its antiprotozoal activities, APL (1) was found to be the most active on Leishmania donovani and L. major promastigotes with EC50 values of 16.3 and 8.2 µM, respectively. Against Trypanosoma brucei brucei trypomastigote forms, the activity of APL was moderated (MEC = 38.0 µM). Its hemisynthetic ester acetic derivative (1c) was 2-42 times more active than that of the APL and reference drugs, justifying further in vivo evaluation of the two compounds (1 and 1c) on Leishmania sp and Trypanosoma brucei brucei/mice models.
- Published
- 2020
14. Expression Pattern of the Pneumocystis jirovecii Major Surface Glycoprotein Superfamily in Patients with Pneumonia
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Emanuel Schmid-Siegert, Sophie Richard, Marco Pagni, Amanda Luraschi, Konrad Mühlethaler, and Philippe M. Hauser
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0301 basic medicine ,Gene isoform ,030106 microbiology ,Population ,Pneumocystis carinii ,Polymorphism, Single Nucleotide ,Genome ,Fungal Proteins ,03 medical and health sciences ,Gene Expression Regulation, Fungal ,Antigenic variation ,Humans ,Immunology and Allergy ,Pneumocystis jirovecii ,610 Medicine & health ,education ,Gene ,Genomic organization ,Genetics ,chemistry.chemical_classification ,education.field_of_study ,Membrane Glycoproteins ,biology ,Pneumonia, Pneumocystis ,Genetic Variation ,biology.organism_classification ,030104 developmental biology ,Infectious Diseases ,chemistry ,Multigene Family ,RNAseq ,colonization factor ,surface antigenic variation ,virulence factor ,Host-Pathogen Interactions ,570 Life sciences ,Glycoprotein - Abstract
Background The human pathogen Pneumocystis jirovecii harbors 6 families of major surface glycoproteins (MSGs) encoded by a single gene superfamily. MSGs are presumably responsible for antigenic variation and adhesion to host cells. The genomic organization suggests that a single member of family I is expressed at a given time per cell, whereas members of the other families are simultaneously expressed. Methods We analyzed RNA sequences expressed in several clinical samples, using specific weighted profiles for sorting of reads and calling of single-nucleotide variants to estimate the diversity of the expressed genes. Results A number of different isoforms of at least 4 MSG families were expressed simultaneously, including isoforms of family I, for which confirmation was obtained in the wet laboratory. Conclusion These observations suggest that every single P. jirovecii population is made of individual cells with distinct surface properties. Our results enhance our understanding of the unique antigenic variation system and cell surface structure of P. jirovecii.
- Published
- 2020
15. A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome
- Author
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Ann Seman, Rixa Woitschach, Duygu Selcen, Divya Nair, Lauren Gunderson, Mahim Jain, Sha Tang, Giuseppe Zampino, Julien L. Marcadier, Marielle Alders, Jason Pinner, Melanie Napier, Linda Hasadsri, Marina Macchiaiolo, Alyssa Blesson, Pavel N. Pichurin, Joseph T. Alaimo, Arjan Bouman, Philippe M. Campeau, Catherine Karimov, Chitra Prasad, Anne Dieux-Coeslier, Nicole L. Bertsch, Bernd Wollnik, Janine Altmüller, Zöe Powis, Holly Dubbs, Tahsin Stefan Barakat, Gregory M. Cooper, Kristen J. Rasmussen, Perrine Brunelle, Patrick R. Blackburn, Erica D. Smith, Jeff M. Milunsky, Katja Kloth, E. Martina Bebin, Lot Snijders Blok, Knut Brockmann, Karin Weiss, Xilma R. Ortiz-Gonzalez, Danna Gal, Dong Li, Francesca Clementina Radio, Joan M. Stoler, Elaine H. Zackai, Jiddeke M. van de Kamp, Deepali N. Shinde, Huifang Yan, Thomas Smol, Alejandro Ferrer, Dagmar Weise, Baiba Lace, Deborah L. Renaud, Lauren E. Bartik, Beth Keena, Michelle L. Thompson, Carol J Saunders, Theodore G. Drivas, Elizabeth J. Bhoj, Eric T. Rush, Marco Tartaglia, Eric W. Klee, Margit Burmeister, Jingmin Wang, Jonas Denecke, Clinical genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, and Clinical Genetics
- Subjects
Adult ,Male ,CHD3 variants ,Genetic testing ,Adolescent ,Snijders Blok-Campeau syndrome ,Developmental Disabilities ,medicine.disease_cause ,Pediatrics ,Article ,Chromodomain ,Craniofacial Abnormalities ,Catalytic Domain ,Intellectual Disability ,Genetics ,medicine ,Missense mutation ,Humans ,Child ,Genetics (clinical) ,Mutation ,medicine.diagnostic_test ,biology ,Significant difference ,DNA Helicases ,Helicase ,Infant ,Syndrome ,Autism spectrum disorders ,Phenotype ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Child, Preschool ,Cohort ,biology.protein ,Female ,Mi-2 Nucleosome Remodeling and Deacetylase Complex - Abstract
There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
- Published
- 2020
16. Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction
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Caroline Nava, Justine Rousseau, Hugo J. Bellen, Yi Ting Cheng, Jiani Chen, Julia Wang, Philippe M. Campeau, Zhongyuan Zuo, Fowzan S. Alkuraya, Weimin Bi, Eissa Faqeih, Alexandra Afenjar, Lee-Jun C. Wong, Klaas J. Wierenga, Jill A. Rosenfeld, Jane Juusola, Joseph G. Gleeson, Sophie Ehresmann, Boris Keren, Diane Doummar, David Li-Kroeger, Ye Jin Park, Emily Kim, Markus Grompe, and Lita Duraine
- Subjects
Adult ,Male ,0301 basic medicine ,Adolescent ,Mutant ,Biology ,medicine.disease_cause ,Article ,Mitochondrial Proteins ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cerebellar Diseases ,Genetics ,medicine ,Animals ,Humans ,V-ATPase ,Global developmental delay ,Child ,Gene ,Genetics (clinical) ,Fibroblasts ,Phenotype ,Pedigree ,Cell biology ,Oxidative Stress ,Drosophila melanogaster ,030104 developmental biology ,Speech delay ,Female ,Cerebellar atrophy ,Atrophy ,Nervous System Diseases ,medicine.symptom ,Lysosomes ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.
- Published
- 2019
17. Trichomonas vaginalis Motility Is Blocked by Drug-Free Thermosensitive Hydrogel
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Philippe M. Loiseau, Sophia Malli, and Kawthar Bouchemal
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0301 basic medicine ,Infectivity ,biology ,Chemistry ,Cilium ,030106 microbiology ,Cell ,Motility ,Flagellum ,biology.organism_classification ,medicine.disease_cause ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,medicine ,Parasite hosting ,Trichomonas vaginalis ,Bacteria - Abstract
Trichomonas vaginalis motility in biological fluids plays a prominent, but understudied, role in parasite infectivity. In this study, the ability of a thermosensitive hydrogel (pluronic F127) to physically immobilize T. vaginalis was investigated. Blocking parasite motility could prevent its attachment to the mucosa, thus reducing the acquisition of the infection. The trajectory of individual parasites was monitored by multiple particle tracking. Mean square displacement, diffusivity, and velocity were calculated from x, y coordinates during time. Major results are that T. vaginalis exhibited different types of trajectories in a diluted solution composed of lactate buffer similar to "run-and-tumble" motion reported for flagellated bacteria. The fastest T. vaginalis specimen moves with a velocity of 19 μm/s. Observation of T. vaginalis movements showed that the cell body remains rigid during swimming and that the propulsive forces necessary to generate the movement are the result of flagellar beating. Parasite motility was partially slowed down using hydroxyethylcellulose hydrogel, used as a reference for the development of vaginal microbicides, while 100% of T. vaginalis were immobile in F127 hydrogel. Once completed by biological investigations on mice, this report suggests using drug-free formulation composed of F127 as a new strategy to prevent T. vaginalis attachment to the mucosa. The concept will be extended to other flagellated organisms where the motility is driven by cilia and flagella.
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- 2019
18. A variant of neonatal progeroid syndrome, or Wiedemann–Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL
- Author
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Sophie Ehresmann, Hyunyun Kim, Virginie Saillour, Smrithi Salian, Guylaine DʹAmours, Philippe M. Campeau, Julie Gauthier, Jean-François Soucy, Grant A. Mitchell, Eliane Beauregard-Lacroix, Geneviève Bernard, and Jacques L. Michaud
- Subjects
media_common.quotation_subject ,Nonsense ,Biology ,Article ,Neonatal Progeroid Syndrome ,03 medical and health sciences ,Progeria ,0302 clinical medicine ,Protein Domains ,Genetics ,medicine ,Humans ,Allele ,Gene ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,media_common ,0303 health sciences ,Fetal Growth Retardation ,RNA Polymerase III ,RNA ,medicine.disease ,Phenotype ,3. Good health ,Codon, Nonsense ,Child, Preschool ,Female ,Lipodystrophy ,030217 neurology & neurosurgery - Abstract
Neonatal progeroid syndrome, also known as Wiedemann–Rautenstrauch syndrome, is a rare condition characterized by severe growth retardation, apparent macrocephaly with prominent scalp veins, and lipodystrophy. It is caused by biallelic variants in POLR3A, a gene encoding for a subunit of RNA polymerase III. All variants reported in the literature lead to at least a partial loss-of-function (when considering both alleles together). Here, we describe an individual with several clinical features of neonatal progeroid syndrome in whom exome sequencing revealed a homozygous nonsense variant in POLR3GL (NM_032305.2:c.358C>T; p.(Arg120Ter)). POLR3GL also encodes a subunit of RNA polymerase III and has recently been associated with endosteal hyperostosis and oligodontia in three patients with a phenotype distinct from the patient described here. Given the important role of POLR3GL in the same complex as the protein implicated in neonatal progeroid syndrome, the nature of the variant identified, our RNA studies suggesting nonsense-mediated decay, and the clinical overlap, we propose POLR3GL as a gene causing a variant of neonatal progeroid syndrome and therefore expand the phenotype associated with POLR3GL variants.
- Published
- 2019
19. Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1
- Author
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Delphine Héron, Wendy Mears, Smrithi Salian, William Boyce Burns, Julia Russo, Elliot S. Stolerman, Valentina Serpieri, David A. Dyment, Philippe M. Campeau, Susanne Morlot, Kristin Herman, Thi Tuyet Mai Nguyen, Ginevra Zanni, Boris Keren, Rachel Rock, Raffaella Cusmai, Efrat Sofrin-Drucker, Hannah Wallaschek, Alison M.R. Castle, Julie R. Jones, Devon L. Johnstone, Haim Bassan, Children's Hospital of Eastern Ontario, CHU Sainte Justine [Montréal], Tel Aviv University [Tel Aviv], University of California, Bambino Gesù Children’s Hospital [Rome, Italy], Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique médicale [CHU Pitié-Salpêtrière], Hannover Medical School [Hannover] (MHH), BC Children's Hospital Research Institute [Vancouver, BC, Canada] (BCCHR), University of British Columbia (UBC), The Greenwood Genetic Center, University of Pavia, and IRCCS Mondino Foundation
- Subjects
Genetics ,0303 health sciences ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,medicine.diagnostic_test ,Glycosylphosphatidylinositol ,Developmental disorders ,Biology ,Phenotype ,Hypotonia ,Clinical knowledge ,Flow cytometry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Neuroimaging ,All Genetics ,medicine ,Alkaline phosphatase ,Neurology (clinical) ,Functional studies ,medicine.symptom ,030217 neurology & neurosurgery ,Genetics (clinical) ,030304 developmental biology - Abstract
Background and ObjectivesTo expand the clinical knowledge of GPAA1-related glycosylphosphatidylinositol (GPI) deficiency.MethodsAn international case series of 7 patients with biallelic GPAA1 variants were identified. Clinical, biochemical, and neuroimaging data were collected for comparison. Where possible, GPI-anchored proteins were assessed using flow cytometry.ResultsTen novel variants were identified in 7 patients. Flow cytometry samples of 3 available patients confirmed deficiency of several GPI-anchored proteins on leukocytes. Extensive phenotypic information was available for each patient. The majority experienced developmental delay, seizures, and hypotonia. Neuroimaging revealed cerebellar anomalies in the majority of the patients. Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects. We notably describe individuals either less affected or older than the ones published previously.DiscussionClinical features of the cases reported broaden the spectrum of the known phenotype of GPAA1-related GPI deficiency, while outlining the importance of using functional studies such as flow cytometry to aid in variant classification.
- Published
- 2021
20. Intranasal vaccine from whole Leishmania donovani antigens provides protection and induces specific immune response against visceral leishmaniasis
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Doumet Georges Helou, François Fasquelle, Juliane Sousa Lanza, Aurélie Mauras, Didier Betbeder, Philippe M. Loiseau, and Sandrine Cojean
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Life Cycles ,Physiology ,RC955-962 ,Antibodies, Protozoan ,Protozoology ,Adaptive Immunity ,White Blood Cells ,Mice ,Medical Conditions ,Animal Cells ,Bone Marrow ,Arctic medicine. Tropical medicine ,Zoonoses ,Immune Physiology ,Medicine and Health Sciences ,Cytotoxic T cell ,Leishmaniasis ,Immune Response ,Vaccines ,Mice, Inbred BALB C ,T Cells ,Acquired immune system ,Infectious Diseases ,Liver ,Leishmaniasis, Visceral ,Protozoan Life Cycles ,Female ,Public aspects of medicine ,RA1-1270 ,Cellular Types ,Research Article ,Neglected Tropical Diseases ,Infectious Disease Control ,Immune Cells ,Immunology ,Leishmania donovani ,Cytotoxic T cells ,Antigens, Protozoan ,Biology ,Microbiology ,Interferon-gamma ,Immune system ,Antigen ,Adjuvants, Immunologic ,medicine ,Parasitic Diseases ,Animals ,Leishmaniasis Vaccines ,Administration, Intranasal ,Protozoan Infections ,Blood Cells ,Promastigotes ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,Cell Biology ,biology.organism_classification ,medicine.disease ,Leishmania ,Tropical Diseases ,Visceral leishmaniasis ,Immunization ,Spleen ,Developmental Biology - Abstract
Visceral leishmaniasis is a protozoan disease associated with high fatality rate in developing countries. Although the drug pipeline is constantly improving, available treatments are costly and live-threatening side effects are not uncommon. Moreover, an approved vaccine against human leishmaniasis does not exist yet. Using whole antigens from Leishmania donovani promastigotes (LdAg), we investigated the protective potential of a novel adjuvant-free vaccine strategy. Immunization of mice with LdAg via the intradermal or the intranasal route prior to infection decreases the parasitic burden in primary affected internal organs, including the liver, spleen, and bone marrow. Interestingly, the intranasal route is more efficient than the intradermal route, leading to better parasite clearance and remarkable induction of adaptive immune cells, notably the helper and cytotoxic T cells. In vitro restimulation experiments with Leishmania antigens led to significant IFN-γ secretion by splenocytes; therefore, exemplifying specificity of the adaptive immune response. To improve mucosal delivery and the immunogenic aspects of our vaccine strategy, we used polysaccharide-based nanoparticles (NP) that carry the antigens. The NP-LdAg formulation is remarkably taken up by dendritic cells and induces their maturation in vitro, as revealed by the increased expression of CD80, CD86 and MHC II. Intranasal immunization with NP-LdAg does not improve the parasite clearance in our experimental timeline; however, it does increase the percentage of effector and memory T helper cells in the spleen, suggesting a potential induction of long-term memory. Altogether, this study provides a simple and cost-effective vaccine strategy against visceral leishmaniasis based on LdAg administration via the intranasal route, which could be applicable to other parasitic diseases., Author summary Visceral leishmaniasis is a neglected tropical disease caused by specific species of Leishmania parasites that affect internal organs including spleen, liver, and bone marrow. The infective stage called promastigote, is transmitted into the host skin via sandfly bites. Visceral leishmaniasis is usually associated with high mortality rate in poor and developing countries, lacking proper health assistance. Moreover, treatments are expensive while no approved vaccines exist to prevent infection and avoid disease outbreaks. This study suggests an affordable and adjuvant-free vaccine formulation made from the total lysate of promastigotes. Vaccine administration via the intranasal route, ensures a remarkable clearance of Leishmania parasites from the internal organs of infected experimental mice. In particular, intranasal route known to be not invasive, is efficient in inducing adequate immune response against the infective form of the parasite. Further studies are now required to improve this prophylactic vaccine and provide therefore the basis for a promising translational approach.
- Published
- 2021
21. Author response for 'Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins'
- Author
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Martine Doco-Fenzy, Smrithi Salian, Emma Palmer, Mariasavina Severino, Beth Hudson, Elisabetta Amadori, Martin Jakob Larsen, Christina Fagerberg, Lene Sperling, Lucas Herissant, Thi Tuyet Mai Nguyen, Carlo Minetti, Rani Sachdev, Anna C.E. Hurst, Valeria Capra, Annalaura Torella, Ieva Miceikaite, Pasquale Striano, Megan Boothe, Melanie Jennesson, Andrea Accogli, Vincenzo Nigro, Marcello Scala, Philippe M. Campeau, Tawfeg Ben-Omran, and Michele Pinelli
- Subjects
Genetics ,Epileptic encephalopathy ,Functional impact ,Biology ,Gpi anchored protein ,Genotype phenotype - Published
- 2021
22. Pneumocystis Mating-Type Locus and Sexual Cycle during Infection
- Author
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Philippe M. Hauser
- Subjects
Homothallism ,Review ,Microbiology ,Airborne transmission ,03 medical and health sciences ,medicine ,Antigenic variation ,Pneumocystis jirovecii ,Animals ,Humans ,DNA, Fungal ,Molecular Biology ,Lung ,030304 developmental biology ,0303 health sciences ,Life Cycle Stages ,biology ,Obligate ,030306 microbiology ,Pneumocystis ,Reproduction ,biology.organism_classification ,medicine.disease ,Sexual reproduction ,Obligate parasite ,Pneumocystis Infections ,Infectious Diseases ,Genome, Fungal ,Pneumonia (non-human) - Abstract
Pneumocystis species colonize mammalian lungs and cause deadly pneumonia if the immune system of the host weakens. Each species presents a specificity for a single mammalian host species. Pneumocystis jirovecii infects humans and provokes pneumonia, which is among the most frequent invasive fungal infections. The lack of in vitro culture methods for these fungi complicates their study. Recently, high-throughput sequencing technologies followed by comparative genomics have allowed a better understanding of the mechanisms involved in the sexuality of Pneumocystis organisms. The structure of their mating-type locus corresponding to a fusion of two loci, Plus and Minus, and the concomitant expression of the three mating-type genes revealed that their mode of sexual reproduction is primarily homothallism. This mode is favored by microbial pathogens and involves a single self-compatible mating type that can enter into the sexual cycle on its own. Pneumocystis sexuality is obligatory within the host's lungs during pneumonia in adults, primary infection in children, and possibly colonization. This sexuality participates in cell proliferation, airborne transmission to new hosts, and probably antigenic variation, processes that are crucial to ensure the survival of the fungus. Thus, sexuality is central in the Pneumocystis life cycle. The obligate biotrophic parasitism with obligate sexuality of Pneumocystis is unique among fungi pathogenic to humans. Pneumocystis organisms are similar to the plant fungal obligate biotrophs that complete their entire life cycle within their hosts, including sex, and that are also difficult to grow in vitro.
- Published
- 2021
23. The calcium‐activated protease calpain regulates netrin‐1 receptor deleted in colorectal cancer‐induced axon outgrowth in cortical neurons
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Nathalie Lamarche-Vane and Philippe M. Duquette
- Subjects
0301 basic medicine ,Deleted in Colorectal Cancer ,Neurogenesis ,Growth Cones ,Neuronal Outgrowth ,Biochemistry ,Rats, Sprague-Dawley ,Focal adhesion ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Netrin ,medicine ,Animals ,Spectrin ,Axon ,Growth cone ,Cerebral Cortex ,Neurons ,biology ,Calpain ,Chemistry ,fungi ,Netrin-1 ,DCC Receptor ,Actin cytoskeleton ,Rats ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,biology.protein ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
During development, neurons extend axons toward their appropriate synaptic targets to establish functional neuronal connections. The growth cone, a highly motile structure at the tip of the axon, is capable of recognizing extracellular guidance cues and translating them into directed axon outgrowth through modulation of the actin cytoskeleton. Netrin-1 mediates its attractive function through the receptor deleted in colorectal cancer (DCC) to promote axon outgrowth and guidance. The calcium-activated protease calpain is involved in the cleavage of cytoskeletal proteins, which plays an important role during adhesion turnover and cell migration. However, its function during neuronal development is less understood. Here we demonstrate that netrin-1 activated calpain in embryonic rat cortical neurons in an extracellular-regulated kinase 1/2-dependent manner. In addition, we found that netrin-1 stimulation led to an increase in calpain-1 localization in the axon, whereas its endogenous inhibitor calpastatin was decreased in the growth cones of cortical neurons by indirect immunofluorescence. Interestingly, calpain-1 was able to cleave DCC in vitro. Furthermore, netrin-1 induced the cleavage of the cytoskeletal proteins spectrin and focal adhesion kinase concomitantly with the intracellular domain of DCC in a calpain-dependent manner in embryonic rat cortical neurons. Cortical neurons over-expressing calpastatin or calpain-depleted neurons displayed increased basal axon length and were unresponsive to netrin-1 stimulation. Altogether, we propose a novel model whereby netrin-1/DCC-mediated axon outgrowth is modulated by calpain-mediated proteolysis of DCC and cytoskeletal targets in embryonic cortical neurons. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.
- Published
- 2019
24. Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca2+-Activated K+ Channel SK3 Cause Zimmermann-Laband Syndrome
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Susan M. White, Janine Altmüller, Pauline E. Schneeberger, Fanny Kortüm, Philippe M. Campeau, Jennifer Keller-Ramey, Kerstin Kutsche, Christiane K. Bauer, Laura A. Baker, Fernando Santos-Simarro, and Karen W. Gripp
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0301 basic medicine ,Hypertrichosis ,Zimmermann–Laband syndrome ,Calmodulin ,biology ,Chemistry ,Mutant ,Protein phosphatase 2 ,medicine.disease ,Molecular biology ,Potassium channel ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,SK3 ,Genetics ,medicine ,biology.protein ,Missense mutation ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
Zimmermann-Laband syndrome (ZLS) is characterized by coarse facial features with gingival enlargement, intellectual disability (ID), hypertrichosis, and hypoplasia or aplasia of nails and terminal phalanges. De novo missense mutations in KCNH1 and KCNK4, encoding K+ channels, have been identified in subjects with ZLS and ZLS-like phenotype, respectively. We report de novo missense variants in KCNN3 in three individuals with typical clinical features of ZLS. KCNN3 (SK3/KCa2.3) constitutes one of three members of the small-conductance Ca2+-activated K+ (SK) channels that are part of a multiprotein complex consisting of the pore-forming channel subunits, the constitutively bound Ca2+ sensor calmodulin, protein kinase CK2, and protein phosphatase 2A. CK2 modulates Ca2+ sensitivity of the channels by phosphorylating SK-bound calmodulin. Patch-clamp whole-cell recordings of KCNN3 channel-expressing CHO cells demonstrated that disease-associated mutations result in gain of function of the mutant channels, characterized by increased Ca2+ sensitivity leading to faster and more complete activation of KCNN3 mutant channels. Pretreatment of cells with the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole revealed basal inhibition of wild-type and mutant KCNN3 channels by CK2. Analogous experiments with the KCNN3 p.Val450Leu mutant previously identified in a family with portal hypertension indicated basal constitutive channel activity and thus a different gain-of-function mechanism compared to the ZLS-associated mutant channels. With the report on de novo KCNK4 mutations in subjects with facial dysmorphism, hypertrichosis, epilepsy, ID, and gingival overgrowth, we propose to combine the phenotypes caused by mutations in KCNH1, KCNK4, and KCNN3 in a group of neurological potassium channelopathies caused by an increase in K+ conductance.
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- 2019
25. Topically Applied Chitosan-Coated Poly(isobutylcyanoacrylate) Nanoparticles Are Active Against Cutaneous Leishmaniasis by Accelerating Lesion Healing and Reducing the Parasitic Load
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Kawthar Bouchemal, Philippe M. Loiseau, Antonio Da Costa, Yasmine Ayadi, Sébastien Pomel, Sophia Malli, Claudine Deloménie, Institut Galien Paris-Sud (IGPS), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut Paris Saclay d’Innovation Thérapeutique (IPSIT), Unité de Catalyse et Chimie du Solide - UMR 8181 (UCCS), and Université d'Artois (UA)-Centrale Lille-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
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Biomedical Engineering ,Pharmacology ,Biomaterials ,Chitosan ,Lesion ,chemistry.chemical_compound ,Cutaneous leishmaniasis ,In vivo ,medicine ,Leishmania major ,Amastigote ,leishmaniasis ,biology ,Biochemistry (medical) ,Leishmaniasis ,[CHIM.CATA]Chemical Sciences/Catalysis ,General Chemistry ,medicine.disease ,biology.organism_classification ,In vitro ,chemistry ,nanoparticles ,chitosan ,medicine.symptom ,poly(isobutylcyanoacrylate) - Abstract
International audience; Parenteral administration of amphotericin B-deoxycholate (AmB-DOC) or pentavalent antimonials to cure cutaneous leishmaniasis (CL) results in severe adverse reactions, while topically applied antileishmanial drugs are ineffective despite their good tolerance. This work is aimed to investigate whether poly(isobutylcyanoacrylate) nanoparticles coated with chitosan (Cs-NPs) could provide intrinsic antileishmanial activity after topical application. In vitro evaluations revealed that nanoparticles were active against the promastigote, axenic amastigote, and intramacrophage forms of Leishmania major. In vivo evaluations after repetitive topical applications on the skin of mice infected with L. major showed that Cs-NPs combined or not with AmB-DOC allowed partial healing of the lesion characterized by histological analyses. The parasitic load of skin specimens collected from mice was significantly reduced compared with that from nontreated mice, as analyzed by quantitative polymerase chain reaction (q-PCR). Ultrastructure characterizations by electron microscopy of L. major promastigotes after incubation with Cs-NPs showed morphological alterations, including aberrant shape and swelling of mitochondria and parasitic vacuoles.
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- 2019
26. Combination of amphotericin B and chitosan platelets for the treatment of experimental cutaneous leishmaniasis: Histological and immunohistochemical examinations
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Indira Dennemont, Philippe M. Loiseau, Kawthar Bouchemal, Sophia Malli, and Sébastien Pomel
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biology ,technology, industry, and agriculture ,Pharmaceutical Science ,Leishmaniasis ,02 engineering and technology ,Pharmacology ,021001 nanoscience & nanotechnology ,medicine.disease ,biology.organism_classification ,030226 pharmacology & pharmacy ,Chitosan ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Cutaneous leishmaniasis ,Amphotericin B ,parasitic diseases ,medicine ,Platelet ,Leishmania major ,0210 nano-technology ,Amastigote ,Candida albicans ,medicine.drug - Abstract
Cutaneous leishmaniasis (CL) is a chronic infectious disease caused by protozoa of the genus Leishmania. Although amphotericin B-deoxycholate (AmB-DOC) showed its ability to partially cure the infection after intravenous administration, it can lead to dose-limiting side-effects (mainly nephorotoxicity). Previous data from our group showed that chitosan particles with typical flat surfaces, called platelets acted as a booster of AmB-DOC activity against Candida albicans and C. glabrata. Platelets were obtained by a hierarchical self-assembly process between chitosan hydrophobically-modified with oleic acid and α-cyclodextrin in water. The objective of this work is to investigate whether chitosan platelets are active against CL, alone or in combination with AmB-DOC. In vitro evaluations showed that platelets exhibited intrinsic antiparasitic activity, while native chitosan was inactive. When combined with AmB-DOC, chitosan platelets exerted an additive effect against Leishmania major amastigote (Fractional inhibitory concentration index FICI = 1.213). Histological and immunohistochemical examinations of skin lesions of mice infected with L. major and treated with the combination showed a significant decrease of the inflammatory granuloma and a reduction of the parasitic load, in comparison with AmB-DOC alone. Our work provides histological and immunohistochemical evidences that the combination of chitosan platelets and AmB could be considered as a strategy to cure CL.
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- 2019
27. A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies
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Shane McKee, Christel Depienne, Diana Baralle, Ddd Study, Justine Rousseau, Philippe M. Campeau, Sophie Ehresmann, Naomichi Matsumoto, Solveig Heide, Max H. Stone, Hannah Titheradge, Alyssa Ritter, Kevin C J Nixon, Seiji Mizuno, Jamie M. Kramer, Delphine Héron, Noriko Miyake, Mohammed Sarikahya, Kosuke Izumi, Western University [London, ON, Canada], Centre Hospitalier Universitaire Sainte-Justine [Montréal, QC, Canada] (CHU Sainte-Justine), Yokohama City University (YCU), University of Southampton, Belfast City Hospital, Children’s Hospital of Philadelphia (CHOP ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Duisburg-Essen, and Birmingham Women's and Children's NHS Foundation Trust
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Male ,Chromosomal Proteins, Non-Histone ,Developmental Disabilities ,Medizin ,Transcriptome ,0302 clinical medicine ,Neurodevelopmental disorder ,Drosophila Proteins ,Child ,Genetics (clinical) ,Exome sequencing ,Neurons ,Regulation of gene expression ,Genetics ,0303 health sciences ,Syndrome ,SWI/SNF ,Hypotonia ,Drosophila melanogaster ,intellectual disability ,Child, Preschool ,Muscle Hypotonia ,Female ,medicine.symptom ,BAFopathies ,Mitosis ,Context (language use) ,SMARCD1 ,Biology ,Drosophila mushroom body ,Article ,Chromatin remodeling ,03 medical and health sciences ,long-term memory ,Memory ,medicine ,Animals ,Humans ,Learning ,Mushroom Bodies ,030304 developmental biology ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,fungi ,medicine.disease ,neurodevelopmental disorder ,Disease Models, Animal ,Gene Expression Regulation ,Neurodevelopmental Disorders ,Mutation ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on 5 individuals with mutations in SMARCD1, presenting with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. The mutations were proven to be de novo in 4 of the 5 individuals, by trio exome sequencing. Mutations in other SWI/SNF components cause Coffin-Siris syndrome and Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack the typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog, Bap60, in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom body specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify a NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development that is essential in establishing neuronal circuits that are required for learning and memory.
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- 2019
28. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability
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Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
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CHROMATIN ,Male ,0301 basic medicine ,Autism ,Sequence Homology ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Medical and Health Sciences ,0302 clinical medicine ,SCHIZOPHRENIA ,Gene expression ,2.1 Biological and endogenous factors ,Missense mutation ,Aetiology ,Child ,de novo variants ,Genetics (clinical) ,Pediatric ,Genetics & Heredity ,Genetics ,biology ,neurodevelopmental disorders ,histone acetylation ,Adaptor Proteins ,Nuclear Proteins ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Syndrome ,Biological Sciences ,Prognosis ,Phenotype ,Chromatin ,Mental Health ,Histone ,intellectual disability ,Child, Preschool ,Female ,REGULATOR ,congenital malformations ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,BRAIN-DEVELOPMENT ,Adult ,Adolescent ,Histone acetyltransferase complex ,Intellectual and Developmental Disabilities (IDD) ,Mutation, Missense ,Deciphering Developmental Disorders study ,autism spectrum disorder ,KAT6B ,RNAI SCREEN ,Young Adult ,03 medical and health sciences ,CAUSES Study ,Rare Diseases ,Intellectual Disability ,Report ,COFACTOR ,medicine ,RUBINSTEIN-TAYBI-SYNDROME ,Humans ,Amino Acid Sequence ,Autistic Disorder ,Preschool ,Gene ,Genetic Association Studies ,Adaptor Proteins, Signal Transducing ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Rubinstein–Taybi syndrome ,Signal Transducing ,Neurosciences ,Infant ,medicine.disease ,TRRAP ,Brain Disorders ,SELF-RENEWAL ,030104 developmental biology ,DE-NOVO MUTATIONS ,Mutation ,biology.protein ,Missense ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
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- 2019
29. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
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Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, McRae, Jeremy F., Clayton, Stephen, Fitzgerald, Tomas W., Kaplanis, Joanna, Prigmore, Elena, Rajan, Diana, Sifrim, Alejandro, Aitken, Stuart, Akawi, Nadia, Alvi, Mohsan, Ambridge, Kirsty, Barrett, Daniel M., Bayzetinova, Tanya, Jones, Philip, Jones, Wendy D., King, Daniel, Krishnappa, Netravathi, Mason, Laura E., Singh, Tarjinder, Tivey, Adrian R., Ahmed, Munaza, Anjum, Uruj, Archer, Hayley, Armstrong, Ruth, Awada, Jana, Balasubramanian, Meena, Banka, Siddharth, Baralle, Diana, Barnicoat, Angela, Batstone, Paul, Baty, David, Bennett, Chris, Berg, Jonathan, Bernhard, Birgitta, Bevan, A. Paul, Bitner-Glindzicz, Maria, Blair, Edward, Blyth, Moira, Bohanna, David, Bourdon, Louise, Bourn, David, Bradley, Lisa, Brady, Angela, Brent, Simon, Brewer, Carole, Brunstrom, Kate, Bunyan, David J., Burn, John, Canham, Natalie, Castle, Bruce, Chandler, Kate, Chatzimichali, Elena, Cilliers, Deirdre, Clarke, Angus, Clasper, Susan, Clayton-Smith, Jill, Clowes, Virginia, Coates, Andrea, Cole, Trevor, Colgiu, Irina, Collins, Amanda, Collinson, Morag N., Connell, Fiona, Cooper, Nicola, Cox, Helen, Cresswell, Lara, Cross, Gareth, Crow, Yanick, D’Alessandro, Mariella, Dabir, Tabib, Davidson, Rosemarie, Davies, Sally, de Vries, Dylan, Dean, John, Deshpande, Charu, Devlin, Gemma, Dixit, Abhijit, Dobbie, Angus, Donaldson, Alan, Donnai, Dian, Donnelly, Deirdre, Donnelly, Carina, Douglas, Angela, Douzgou, Sofia, Duncan, Alexis, Eason, Jacqueline, Ellard, Sian, Ellis, Ian, Elmslie, Frances, Evans, Karenza, Everest, Sarah, Fendick, Tina, Fisher, Richard, Flinter, Frances, Foulds, Nicola, Fry, Andrew, Fryer, Alan, Gardiner, Carol, Gaunt, Lorraine, Ghali, Neeti, Gibbons, Richard, Gill, Harinder, Goodship, Judith, Goudie, David, Gray, Emma, Green, Andrew, Greene, Philip, Greenhalgh, Lynn, Gribble, Susan, Harrison, Rachel, Harrison, Lucy, Harrison, Victoria, Hawkins, Rose, He, Liu, Hellens, Stephen, Henderson, Alex, Hewitt, Sarah, Hildyard, Lucy, Hobson, Emma, Holden, Simon, Holder, Muriel, Holder, Susan, Hollingsworth, Georgina, Homfray, Tessa, Humphreys, Mervyn, Hurst, Jane, Hutton, Ben, Ingram, Stuart, Irving, Melita, Islam, Lily, Jackson, Andrew, Jarvis, Joanna, Jenkins, Lucy, Johnson, Diana, Jones, Elizabeth, Josifova, Dragana, Joss, Shelagh, Kaemba, Beckie, Kazembe, Sandra, Kelsell, Rosemary, Kerr, Bronwyn, Kingston, Helen, Kini, Usha, Kinning, Esther, Kirby, Gail, Kirk, Claire, Kivuva, Emma, Kraus, Alison, Kumar, Dhavendra, Kumar, V. K. Ajith, Lachlan, Katherine, Lam, Wayne, Lampe, Anne, Langman, Caroline, Lees, Melissa, Lim, Derek, Longman, Cheryl, Lowther, Gordon, Lynch, Sally A., Magee, Alex, Maher, Eddy, Male, Alison, Mansour, Sahar, Marks, Karen, Martin, Katherine, Maye, Una, McCann, Emma, McConnell, Vivienne, McEntagart, Meriel, McGowan, Ruth, McKay, Kirsten, McKee, Shane, McMullan, Dominic J., McNerlan, Susan, McWilliam, Catherine, Mehta, Sarju, Metcalfe, Kay, Middleton, Anna, Miedzybrodzka, Zosia, Miles, Emma, Mohammed, Shehla, Montgomery, Tara, Moore, David, Morgan, Sian, Morton, Jenny, Mugalaasi, Hood, Murday, Victoria, Murphy, Helen, Naik, Swati, Nemeth, Andrea, Nevitt, Louise, Norman, Andrew, O’Shea, Rosie, Ogilvie, Caroline, Ong, Kai-Ren, Park, Soo-Mi, Parker, Michael J., Patel, Chirag, Paterson, Joan, Payne, Stewart, Perrett, Daniel, Phipps, Julie, Pilz, Daniela T., Pollard, Martin, Pottinger, Caroline, Poulton, Joanna, Pratt, Norman, Prescott, Katrina, Pridham, Abigail, Procter, Annie, Purnell, Hellen, Quarrell, Oliver, Ragge, Nicola, Rahbari, Raheleh, Randall, Josh, Raymond, Lucy, Rice, Debbie, Robert, Leema, Roberts, Eileen, Roberts, Jonathan, Roberts, Paul, Roberts, Gillian, Ross, Alison, Rosser, Elisabeth, Saggar, Anand, Samant, Shalaka, Sampson, Julian, Sandford, Richard, Sarkar, Ajoy, Schweiger, Susann, Scott, Richard, Scurr, Ingrid, Selby, Ann, Seller, Anneke, Sequeira, Cheryl, Shannon, Nora, Sharif, Saba, Shaw-Smith, Charles, Shearing, Emma, Shears, Debbie, Sheridan, Eamonn, Simonic, Ingrid, Singzon, Roldan, Skitt, Zara, Smith, Audrey, Smith, Kath, Smithson, Sarah, Sneddon, Linda, Splitt, Miranda, Squires, Miranda, Stewart, Fiona, Stewart, Helen, Straub, Volker, Suri, Mohnish, Sutton, Vivienne, Swaminathan, Ganesh Jawahar, Sweeney, Elizabeth, Tatton-Brown, Kate, Taylor, Cat, Taylor, Rohan, Tein, Mark, Temple, I. Karen, Thomson, Jenny, Tischkowitz, Marc, Tomkins, Susan, Torokwa, Audrey, Treacy, Becky, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Vandersteen, Anthony, Varghese, Vinod, Vasudevan, Pradeep, Vijayarangakannan, Parthiban, Vogt, Julie, Wakeling, Emma, Wallwark, Sarah, Waters, Jonathon, Weber, Astrid, Wellesley, Diana, Whiteford, Margo, Widaa, Sara, Wilcox, Sarah, Wilkinson, Emily, Williams, Denise, Williams, Nicola, Wilson, Louise, Woods, Geoff, Wragg, Christopher, Wright, Michael, Yates, Laura, Yau, Michael, Nellåker, Chris, Parker, Michael, Firth, Helen V., Wright, Caroline F., FitzPatrick, David R., Barrett, Jeffrey C., Hurles, Matthew E., Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.
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Male ,Models, Molecular ,Developmental Disabilities ,Gene Expression ,General Physics and Astronomy ,02 engineering and technology ,Chromatin remodelling ,Sociology ,lcsh:Science ,Independent research ,Adenosine Triphosphatases ,0303 health sciences ,Multidisciplinary ,biology ,Health innovation ,Disease genetics ,Published Erratum ,Neurodevelopmental disorders ,021001 nanoscience & nanotechnology ,Spelling ,3. Good health ,Phenotype ,General partnership ,Child, Preschool ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Female ,medicine.symptom ,Construct (philosophy) ,0210 nano-technology ,Psychology ,Mi-2 Nucleosome Remodeling and Deacetylase Complex ,Clinical epigenetics ,Genotype ,Science ,Mutation, Missense ,Library science ,Child health ,Speech Disorders ,General Biochemistry, Genetics and Molecular Biology ,Domain (software engineering) ,03 medical and health sciences ,Protein Domains ,Intellectual Disability ,medicine ,Humans ,Author Correction ,030304 developmental biology ,Research ethics ,Language Disorders ,Whole Genome Sequencing ,Core Grant ,Macrocephaly ,DNA Helicases ,Helicase ,General Chemistry ,Chromatin Assembly and Disassembly ,Megalencephaly ,HEK293 Cells ,biology.protein ,lcsh:Q ,Neuroscience ,Impaired speech - Abstract
An Author Correction to this article was published on 15 February 2019 An Author Correction to this article was published on 02 May 2019 We thank all individuals and families for their contribution. We thank Amaia Carrion Castillo and Else Eising for assistance with the WGS analysis of the index individual, and Sarah Graham and Elliot Sollis for cloning the wild-type CHD3 construct for immunofluorescence. This work was supported by the Netherlands Organization for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (S.E.F.), the National Institute on Deafness and Other Communication Disorders Grant DC000496 (L.Sh.) and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (Grant U54 HD090256) to L.Sh., the Canadian Institutes of Health Research Grants MOP-119595 and PJT-148830 to W.T.G. Individuals 11, 16, 24, and 28 were part of The DDD Study cohort. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [Grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The DDD study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.
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- 2019
30. Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay
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Keren Machol, Justine Rousseau, Sophie Ehresmann, Thomas Garcia, Thi Tuyet Mai Nguyen, Rebecca C. Spillmann, Jennifer A. Sullivan, Vandana Shashi, Yong-hui Jiang, Nicholas Stong, Elise Fiala, Marcia Willing, Rolph Pfundt, Tjitske Kleefstra, Megan T. Cho, Heather McLaughlin, Monica Rosello Piera, Carmen Orellana, Francisco Martínez, Alfonso Caro-Llopis, Sandra Monfort, Tony Roscioli, Cheng Yee Nixon, Michael F. Buckley, Anne Turner, Wendy D. Jones, Peter M. van Hasselt, Floris C. Hofstede, Koen L.I. van Gassen, Alice S. Brooks, Marjon A. van Slegtenhorst, Katherine Lachlan, Jessica Sebastian, Suneeta Madan-Khetarpal, Desai Sonal, Naidu Sakkubai, Julien Thevenon, Laurence Faivre, Alice Maurel, Slavé Petrovski, Ian D. Krantz, Jennifer M. Tarpinian, Jill A. Rosenfeld, Brendan H. Lee, Philippe M. Campeau, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Ani Dillon, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Carlos Ferreira, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew R. Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Jean M. Johnston, Angela L. Jones, Isaac S. Kohane, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Allen Lipson, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Matthew Might, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Kimberly Splinter, Joan M. Stoler, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer M. Valivullah, Eric Vilain, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Patricia A. Ward, Katrina M. Waters, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Diane B. Zastrow, Allison Zheng, and Clinical Genetics
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Male ,0301 basic medicine ,Hypertrichosis ,speech delay ,Bafopathy ,Developmental Disabilities ,CACNB4 ,0302 clinical medicine ,Neurodevelopmental disorder ,Intellectual disability ,Bafopathy, developmental delay, dysmorphisms, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorder, speech delay, transcriptome ,Genetics(clinical) ,Child ,Genetics (clinical) ,Genetics ,Syndrome ,Hypotonia ,DNA-Binding Proteins ,developmental delay ,Corticogenesis ,intellectual disability ,Child, Preschool ,Speech delay ,Female ,medicine.symptom ,Hand Deformities, Congenital ,dysmorphisms ,Adolescent ,Micrognathism ,genotype-phenotype correlation ,Biology ,Chromatin remodeling ,03 medical and health sciences ,Journal Article ,medicine ,Humans ,Abnormalities, Multiple ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,medicine.disease ,neurodevelopmental disorder ,Reelin Protein ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,030104 developmental biology ,Face ,Mutation ,biology.protein ,transcriptome ,Neck ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Contains fulltext : 202800.pdf (Publisher’s version ) (Open Access) SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
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- 2019
31. Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy
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Nanda M. Verhoeven-Duif, Janet Koster, Hans R. Waterham, Wyeth W. Wasserman, Justine Rousseau, Judith J.M. Jans, Youdong Wang, Colin J. D. Ross, Mahmoud Y. Issa, Liesbeth T. Wintjes, Maja Tarailo-Graovac, Leo A. J. Kluijtmans, Clara D.M. van Karnebeek, Michèl A.A.P. Willemsen, Jos P.N. Ruiter, Xiao-Yan Wen, Ron A. Wevers, Philippe M. Campeau, Farhad Karbassi, Cristina Skrypnyk, Marleen C. D. G. Huigen, Koroboshka Brand-Arzamendi, Feng Cao, Richard J. Rodenburg, Zhengping Jia, Meng Li, Ronald J.A. Wanders, Ruben Ramos, Britt I. Drögemöller, Maha S. Zaki, Joseph G. Gleeson, Jolita Ciapaite, Robin van der Lee, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ANS - Cellular & Molecular Mechanisms, Paediatric Metabolic Diseases, AGEM - Inborn errors of metabolism, Laboratory Genetic Metabolic Diseases, ARD - Amsterdam Reproduction and Development, APH - Methodology, Pediatric surgery, Amsterdam Neuroscience - Brain Imaging, Amsterdam Reproduction & Development (AR&D), and Laboratory Medicine
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0301 basic medicine ,Male ,Malates ,Malate-aspartate shuttle ,Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] ,Fatty Acid-Binding Proteins ,GOT2 ,Article ,Serine ,03 medical and health sciences ,Mice ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Exome Sequencing ,Genetics ,medicine ,Journal Article ,pyridoxine responsive epilepsy ,Animals ,Humans ,Child ,Zebrafish ,Genetics (clinical) ,Alleles ,Gene knockdown ,Aspartic Acid ,Brain Diseases ,biology ,HEK 293 cells ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Hyperammonemia ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,biology.organism_classification ,Pyridoxine ,medicine.disease ,3. Good health ,Cell biology ,mitochondriopathy ,030104 developmental biology ,HEK293 Cells ,malate-aspartate shuttle ,Child, Preschool ,Gene Knockdown Techniques ,Mutation ,Female ,metabolism ,redox imbalancetreatment ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Early-infantile encephalopathies with epilepsy are devastating conditions mandating an accurate diagnosis to guide proper management. Whole-exome sequencing was used to investigate the disease etiology in four children from independent families with intellectual disability and epilepsy, revealing bi-allelic GOT2 mutations. In-depth metabolic studies in individual 1 showed low plasma serine, hypercitrullinemia, hyperlactatemia, and hyperammonemia. The epilepsy was serine and pyridoxine responsive. Functional consequences of observed mutations were tested by measuring enzyme activity and by cell and animal models. Zebrafish and mouse models were used to validate brain developmental and functional defects and to test therapeutic strategies. GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase. GOT2 enzyme activity was deficient in fibroblasts with bi-allelic mutations. GOT2, a member of the malate-aspartate shuttle, plays an essential role in the intracellular NAD(H) redox balance. De novo serine biosynthesis was impaired in fibroblasts with GOT2 mutations and GOT2-knockout HEK293 cells. Correcting the highly oxidized cytosolic NAD-redox state by pyruvate supplementation restored serine biosynthesis in GOT2-deficient cells. Knockdown of got2a in zebrafish resulted in a brain developmental defect associated with seizure-like electroencephalography spikes, which could be rescued by supplying pyridoxine in embryo water. Both pyridoxine and serine synergistically rescued embryonic developmental defects in zebrafish got2a morphants. The two treated individuals reacted favorably to their treatment. Our data provide a mechanistic basis for the biochemical abnormalities in GOT2 deficiency that may also hold for other MAS defects.
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- 2019
32. Synthesis and biological evaluation against Leishmania donovani of novel hybrid molecules containing indazole-based 2-pyrone scaffolds
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S Cojean, L Bouissane, C Menendez, Souad Mojahidi, M Berkani, M El Ghozlani, A Allam, El Mostapha Rakib, Philippe M. Loiseau, Michel Baltas, Laboratory of Spectrochemistry and Environment, Beni Mellal Faculty of Sciences and Technologies, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Laboratoire de Génie des Procédés et Matériaux - EA 4038 (LGPM), CentraleSupélec, Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), and Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
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Stereochemistry ,Leishmania donovani ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,Acetic acid ,chemistry.chemical_compound ,Drug Discovery ,[CHIM]Chemical Sciences ,Axenic ,Amastigote ,ComputingMilieux_MISCELLANEOUS ,Tetrahydrofuran ,Pharmacology ,Indazole ,biology ,010405 organic chemistry ,Organic Chemistry ,biology.organism_classification ,In vitro ,3. Good health ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,2-Pyrone ,Molecular Medicine - Abstract
A series of novel indazole-pyrone hybrids were synthesized by a one pot reaction between N-alkyl-6(5)-nitroindazoles and 2-pyrone (4-hydroxy-6-methyl-2H-pyran-2-one) using indium or stannous chloride as the reducing system in the presence of acetic acid in tetrahydrofuran. The hybrid molecules were obtained in good to excellent yields (72-92%) and characterized by NMR and single crystal X-ray diffraction. Nineteen compounds were tested in vitro against both Leishmania donovani (MHOM/ET/67/HU3, also called LV9) axenic and intramacrophage amastigotes. Among all, five compounds showed anti-leishmanial activity against intracellular L. donovani with an IC50 in the range of 2.25 to 62.56 μM. 3-(1-(3-Chloro-2-ethyl-2H-indazol-6-ylamino)ethylidene)-6-methyl-3H-pyran-2,4-dione 6f was found to be the most active compound for axenic amastigotes and intramacrophage amastigotes of L. donovani with IC50 values of 2.48 ± 1.02 μM and 2.25 ± 1.89 μM, respectively. However, the cytotoxicity of the most promising compound justifies further pharmacomodulations.
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- 2019
33. Bone autografting in medial open wedge high tibial osteotomy results in improved osseous gap healing on computed tomography, but no functional advantage: a prospective, randomised, controlled trial
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Reto Sutter, Dominik C. Meyer, Philippe M. Tscholl, Peter U. Brucker, Sandro F. Fucentese, Peter P. Koch, University of Zurich, and Fucentese, Sandro F
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Adult ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Knee Joint ,medicine.medical_treatment ,610 Medicine & health ,Bone healing ,Bone grafting ,Osteotomy ,Transplantation, Autologous ,Iliac crest ,Ilium ,03 medical and health sciences ,2732 Orthopedics and Sports Medicine ,0302 clinical medicine ,High tibial osteotomy ,medicine ,Humans ,Knee ,Orthopedics and Sports Medicine ,Postoperative Period ,Prospective Studies ,Varus deformity ,Wound Healing ,030222 orthopedics ,Bone Transplantation ,Tibia ,biology ,business.industry ,030229 sport sciences ,Middle Aged ,Osteoarthritis, Knee ,musculoskeletal system ,medicine.disease ,biology.organism_classification ,2746 Surgery ,Surgery ,Valgus ,medicine.anatomical_structure ,Orthopedic surgery ,Regression Analysis ,Female ,10046 Balgrist University Hospital, Swiss Spinal Cord Injury Center ,Tomography, X-Ray Computed ,business ,Bone Plates - Abstract
Medial open wedge high tibial osteotomy (owHTO) is a valuable surgical technique used to manage medial degeneration in varus knees. Iliac crest autograft is considered the gold standard gap-filler. It was hypothesised that iliac crest autograft promotes gap healing and improves functional outcome in owHTO. Between 2005 and 2009, patients scheduled to undergo owHTO stabilised by a medial locking compression plate were randomised to undergo owHTO either with iliac crest autograft (group A) or without bone void filler (group B). Pre- and postoperative leg axes were recorded. At 3 and 12 months postoperatively, the healing of the osteotomy gap was measured as a percentage on CT images, and functional scores were recorded. There were 15 patients in group A, and 25 in group B. The groups were similar in age, sex ratio, knee varus deformity, body mass index, and smoking status. Group A and B had similar preoperative varus (6.9° vs. 7.6°) and postoperative valgus (2.2° vs. 3.0°). Compared with the control group, group A had a significantly greater degree of osseous gap healing after 3 months (40.1% vs. 10.8%, p = 0.045) and 12 months (91.5% vs. 59.1%, p ≤ 0.001). Multiple linear regression analysis found that bone grafting was an independent promoting factor for gap healing, while increased preoperative varus was an independent retardant factor at 3 months (p = 0.004 and p = 0.002, respectively) and 12 months (p ≤ 0.001 and p = 0.003, respectively). Younger age was a promoting factor for gap healing on CT at 3 months (p ≤ 0.001), but not at 12 months. No correlations were found between bone healing and functional outcome, body mass index, or smoking status. Iliac crest autograft significantly increases healing of the osteotomy gap after owHTO. Increased preoperative varus and older patient age are independent factors that delay early healing of the osteotomy. However, no functional advantage was found at 3 or 12 months postoperatively. Therefore, routine use of iliac crest autograft cannot be recommended. II.
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- 2018
34. Genomics and evolution of Pneumocystis species
- Author
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Philippe M. Hauser and Ousmane H. Cissé
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0301 basic medicine ,Microbiology (medical) ,030106 microbiology ,Population genetics ,Genomics ,Context (language use) ,Biology ,Microbiology ,Genome ,03 medical and health sciences ,Genetic algorithm ,Genetics ,Humans ,Gene family ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Pneumocystis ,Pneumonia, Pneumocystis ,Mating system ,Biological Evolution ,030104 developmental biology ,Infectious Diseases ,Evolutionary biology ,Genome, Fungal ,Adaptation - Abstract
The genus Pneumocystis comprises highly diversified fungal species that cause severe pneumonia in individuals with a deficient immune system. These fungi infect exclusively mammals and present a strict host species specificity. These species have co-diverged with their hosts for long periods of time (> 100 MYA). Details of their biology and evolution are fragmentary mainly because of a lack of an established long-term culture system. Recent genomic advances have unlocked new areas of research and allow new hypotheses to be tested. We review here new findings of the genomic studies in relation with the evolutionary trajectory of these fungi and discuss the impact of genomic data analysis in the context of the population genetics. The combination of slow genome decay and limited expansion of specific gene families and introns reflect intimate interactions of these species with their hosts. The evolutionary adaptation of these organisms is profoundly influenced by their population structure, which in turn is determined by intrinsic features such as their self-fertilizing mating system, high host specificity, long generation times, and transmission mode. Essential key questions concerning their adaptation and speciation remain to be answered. The next cornerstone will consist in the establishment of a long-term culture system and genetic manipulation that should allow unravelling the driving forces of Pneumocystis species evolution.
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- 2018
35. The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons
- Author
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Michael R. Bowl, Elsa Rossignol, Mattéa J. Finelli, Enrico Castroflorio, Lauren Chessum, Davide Aprile, Anna Fassio, Andrew R. Bassett, Alexis Lupien-Meilleur, Philippe M. Campeau, Julia Grasegger, Peter L. Oliver, Matteo T. Degiacomi, Matteo Moschetta, Fabio Benfenati, and Alexander Jeans
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0301 basic medicine ,GTPase-activating protein ,Hearing Loss, Sensorineural ,Nails, Malformed ,Nerve Tissue Proteins ,Haploinsufficiency ,Neurotransmission ,Biology ,Neuronal Transmission ,Craniofacial Abnormalities ,03 medical and health sciences ,Epilepsy ,Mice ,0302 clinical medicine ,DOOR syndrome ,Seizures ,Intellectual Disability ,Genetics ,medicine ,Animals ,Humans ,Exome ,Amino Acid Sequence ,Molecular Biology ,Gene ,Genetics (clinical) ,Regulation of gene expression ,Neurons ,Neuronal Plasticity ,GTPase-Activating Proteins ,Membrane Proteins ,General Medicine ,medicine.disease ,Endocytosis ,Cell biology ,Pedigree ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,Mutation ,General Article ,Carrier Proteins ,Hand Deformities, Congenital ,030217 neurology & neurosurgery - Abstract
Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene are associated with a range of inherited neurological disorders, from drug-refractory lethal epileptic encephalopathy and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures) to non-syndromic hearing loss. TBC1D24 has been implicated in neuronal transmission and maturation, although the molecular function of the gene and the cause of the apparently complex disease spectrum remain unclear. Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically. Here we have systematically investigated an allelic series of disease-associated mutations in neurons alongside a new mouse model to investigate the consequences of TBC1D24 haploinsufficiency to mammalian neurodevelopment and synaptic physiology. The cellular studies reveal that disease-causing mutations that disrupt either of the conserved protein domains in TBC1D24 are implicated in neuronal development and survival and are likely acting as loss-of-function alleles. We then further investigated TBC1D24 haploinsufficiency in vivo and demonstrate that TBC1D24 is also crucial for normal presynaptic function: genetic disruption of Tbc1d24 expression in the mouse leads to an impairment of endocytosis and an enlarged endosomal compartment in neurons with a decrease in spontaneous neurotransmission. These data reveal the essential role for TBC1D24 at the mammalian synapse and help to define common synaptic mechanisms that could underlie the varied effects of TBC1D24 mutations in neurological disease.
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- 2018
36. Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities
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Robin Kuhner, Khalijah Awang, Jérôme Bignon, Philippe M. Loiseau, Cécile Apel, Hélène Levaique, Olivier Pamlard, Marc Litaudon, Margaux Arriola, Sébastien Pomel, CNRS, Centrale Lille, ENSCL, Univ. Artois, Université de Lille, Institut de Chimie des Substances Naturelles [ICSN], Unité de Catalyse et Chimie du Solide (UCCS) - UMR 8181, Biomolécules : Conception, Isolement, Synthèse [BioCIS], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] [UM], Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Centre National de la Recherche Scientifique (CNRS), and Université Paris-Saclay
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natural products ,Antiprotozoal Agents ,Pharmaceutical Science ,GDP-Mannose pyrophosphorylase ,Context (language use) ,Analytical Chemistry ,Chemical library ,Leishmania ,Small Molecule Libraries ,lcsh:QD241-441 ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Drug Discovery ,medicine ,Animals ,Humans ,[CHIM]Chemical Sciences ,Physical and Theoretical Chemistry ,Axenic ,Amastigote ,Leishmaniasis ,IC50 ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,030306 microbiology ,Chemistry ,Communication ,Organic Chemistry ,therapeutic target ,Resorcinols ,alkyl-resorcinol ,biology.organism_classification ,medicine.disease ,Nucleotidyltransferases ,3. Good health ,RAW 264.7 Cells ,Enzyme ,Pharmaceutical Preparations ,Biochemistry ,Chemistry (miscellaneous) ,Molecular Medicine - Abstract
Leishmaniasis is a vector-borne disease caused by the protozoan parasite Leishmania found in tropical and sub-tropical areas, affecting 12 million people around the world. Only few treatments are available against this disease and all of them present issues of toxicity and/or resistance. In this context, the development of new antileishmanial drugs specifically directed against a therapeutic target appears to be a promising strategy. The GDP-Mannose Pyrophosphorylase (GDP-MP) has been previously shown to be an attractive therapeutic target in Leishmania. In this study, a chemical library of 5000 compounds was screened on both L. infantum (LiGDP-MP) and human (hGDP-MP) GDP-MPs. From this screening, oncostemonol D was found to be active on both GDP-MPs at the micromolar level. Ten alkyl-resorcinol derivatives, of which oncostemonols E and J (2 and 3) were described for the first time from nature, were then evaluated on both enzymes as well as on L. infantum axenic and intramacrophage amastigotes. From this evaluation, compounds 1 and 3 inhibited both GDP-MPs at the micromolar level, and compound 9 displayed a three-times lower IC50 on LiGDP-MP, at 11 µM, than on hGDP-MP. As they displayed mild activities on the parasite, these compounds need to be further pharmacomodulated in order to improve their affinity and specificity to the target as well as their antileishmanial activity.
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- 2021
37. Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype–phenotype spectrum and functional impact on GPI-anchored proteins
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Anna C.E. Hurst, Christina Fagerberg, Lene Sperling, Marcello Scala, Lucas Herissant, Martine Doco-Fenzy, Emma Palmer, Beth Hudson, Melanie Jennesson, Martin Jakob Larsen, Elisabetta Amadori, Vincenzo Nigro, Andrea Accogli, Smrithi Salian, Pasquale Striano, Annalaura Torella, Michele Pinelli, Ieva Miceikaite, Megan Boothe, Valeria Capra, Tawfeg Ben-Omran, Mariasavina Severino, Thi Tuyet Mai Nguyen, Carlo Minetti, Rani Sachdev, Philippe M. Campeau, Salian, S., Scala, M., Nguyen, T. T. M., Severino, M., Accogli, A., Amadori, E., Torella, A., Pinelli, M., Hudson, B., Boothe, M., Hurst, A., Ben-Omran, T., Larsen, M. J., Fagerberg, C. R., Sperling, L., Miceikaite, I., Herissant, L., Doco-Fenzy, M., Jennesson, M., Nigro, V., Striano, P., Minetti, C., Sachdev, R. K., Palmer, E. E., Capra, V., and Campeau, P. M.
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Male ,Glycosylphosphatidylinositols ,DNA Mutational Analysis ,Mutant ,Infantile ,Spasms ,Transduction (genetics) ,0302 clinical medicine ,Pregnancy ,Prenatal Diagnosis ,Genetics (clinical) ,0303 health sciences ,Brain ,Magnetic Resonance Imaging ,Hypotonia ,Transmembrane protein ,GPI-anchored proteins ,Pedigree ,3. Good health ,Phenotype ,Female ,medicine.symptom ,Spasms, Infantile ,lentiviral gene rescue ,ARV1 ,early-infantile epileptic encephalopathy ,Alleles ,Amino Acid Substitution ,Carrier Proteins ,Facies ,GPI-Linked Proteins ,Humans ,Membrane Proteins ,Mutation ,Genetic Association Studies ,Genetic Predisposition to Disease ,Encephalopathy ,Biology ,03 medical and health sciences ,Complementary DNA ,Genetics ,medicine ,030304 developmental biology ,GPI-anchored protein ,Endoplasmic reticulum ,Wild type ,medicine.disease ,Molecular biology ,030217 neurology & neurosurgery - Abstract
Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features. Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations. This study expands the clinical and molecular spectrum of the ARV1-related encephalopathy, confirming the essential role of ARV1 in GPI biosynthesis and brain function.
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- 2021
38. Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder
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Erica E. Davis, Xenia Latypova, Damien Lederer, LaDonna Immken, Bertrand Isidor, Carmen Orellana, Nicolette S. den Hollander, Shannon Bell, Francisco Martínez, Alice Molle, Oluwadamilare A. Adebambo, Thomas Besnard, Dmitriy Niyazov, Anne Claude Tabet, Marie Deprez, Kamran Moradkhani, Alfonso Caro, Sandra Mercier, Solène Conrad, Philippe M. Campeau, Xiang-Jiao Yang, Christelle Retière, Nicholas Katsanis, Marie Vincent, Kirsty McWalter, Jill A. Rosenfeld, Raymond J. Louie, Stéphane Bézieau, Cynthia Fourgeux, Sharon F. Suchy, Jagdeep S. Walia, Mónica Roselló, Cédric Le Caignec, Emmelien Aten, Jeremie Poschmann, Benjamin Cogné, Peter Kannu, Miranda Splitt, Pawel Stankiewicz, Yline Capri, Catherine Willem, Tahir N. Khan, Justine Rousseau, Sébastien Küry, Jonathan I. Levy, Roger E. Stevenson, Centre hospitalier universitaire de Nantes (CHU Nantes), Duke University Medical Center, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hospital Universitario y Politécnico La Fe [Valencia, Spain], Ochsner Medical Center [New Orleans, Louisiana, USA], Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Hôpital Robert Debré, The Hospital for sick children [Toronto] (SickKids), Leiden University Medical Center (LUMC), Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Kingston General Health Research Institute [Kingston, ON, Canada] (KGHRI), Dell Children's Medical Group [Austin, TX, USA] (DCMG), Baylor College of Medicine (BCM), Baylor University, GeneDx [Gaithersburg, MD, USA], The Greenwood Genetic Center, Centre Hospitalier Universitaire Sainte-Justine [Montréal, QC, Canada] (CHU Sainte-Justine), EFS Centre-Pays de la Loire [Nantes], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEX IGO Immunothérapie Grand Ouest, McGill University = Université McGill [Montréal, Canada], Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Medical School [Chicago], Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, CHU Sainte Justine [Montréal], Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), and RETIERE, Christelle
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Male ,Models, Molecular ,Autism Spectrum Disorder ,[SDV]Life Sciences [q-bio] ,Haploinsufficiency ,medicine.disease_cause ,Histones ,0302 clinical medicine ,HDAC ,Intellectual disability ,Child ,Zebrafish ,Genetics (clinical) ,Exome sequencing ,Genetics ,0303 health sciences ,Mutation ,HDAC, SIN3A, SINB, acetylation, autism, epigenetics, intellectual disability, mutation, transcription, zebrafish ,Syndrome ,Middle Aged ,Magnetic Resonance Imaging ,[SDV] Life Sciences [q-bio] ,intellectual disability ,Child, Preschool ,Larva ,Female ,transcription ,Adolescent ,DNA Copy Number Variations ,autism ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Histone Deacetylases ,Frameshift mutation ,Young Adult ,03 medical and health sciences ,Report ,medicine ,Animals ,Humans ,Epigenetics ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,030304 developmental biology ,SIN3A ,acetylation ,epigenetics ,Infant ,Zebrafish Proteins ,SINB ,biology.organism_classification ,medicine.disease ,zebrafish ,Repressor Proteins ,Histone deacetylase ,mutation ,030217 neurology & neurosurgery - Abstract
International audience; Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a $230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
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- 2021
39. UBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism
- Author
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Yong Tae Kwon, Ah Jung Heo, Jill A. Rosenfeld, Eliane Beauregard-Lacroix, Carlos A. Bacino, Philippe M. Campeau, Maren Wenzel, Valentina Stanley, Hamad Al Deiab, Michel R. Leroux, Christine Kondratev, Justine Rousseau, Katherine Neas, Brett H. Graham, Matias Wagner, Chunmei Li, Fuad Al Mutairi, Joseph G. Gleeson, and Maha S. Zaki
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0301 basic medicine ,Proteasome Endopeptidase Complex ,Hearing Loss, Sensorineural ,Ubiquitin-Protein Ligases ,Notch signaling pathway ,Nose ,medicine.disease_cause ,Article ,Germline ,Epigenetic ,Epilepsy ,Hypothyroidism ,Kat6b ,Notch ,Ptosis ,Ubr-5 ,Ubr-7 ,Ubr5 ,Ubr7 ,Cell Line ,Anus, Imperforate ,Histones ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Ubiquitin ,Ectodermal Dysplasia ,Intellectual Disability ,Genetics ,medicine ,Animals ,Humans ,Epigenetics ,Caenorhabditis elegans ,Growth Disorders ,Genetics (clinical) ,Mutation ,Receptors, Notch ,biology ,Pancreatic Diseases ,medicine.disease ,Phenotype ,Cell biology ,HEK293 Cells ,030104 developmental biology ,Histone ,Neurodevelopmental Disorders ,biology.protein ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Summary The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1–7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences (“N-end rule”). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.
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- 2021
40. Response to Gao et al
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Philippe M. Campeau and Eliane Beauregard-Lacroix
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Information retrieval ,Text mining ,business.industry ,Biology ,business ,Genetics (clinical) - Published
- 2021
41. Repurposing Auranofin and Evaluation of a New Gold(I) Compound for the Search of Treatment of Human and Cattle Parasitic Diseases: From Protozoa to Helminth Infections
- Author
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David L. Williams, Peter Ziniel, Christina A. Bulman, Alexandre Taravaud, Fidelis Cho-Ngwa, Liwen Feng, Chelsea Fischer, Sébastien Pomel, Perle Latré de Laté, Philippe M. Loiseau, Louis Maes, Judy A. Sakanari, Elisabeth Davioud-Charvet, Centre National de la Recherche Scientifique (CNRS), Laboratoire d'innovation moléculaire et applications (LIMA), and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
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anti-trypanosomal ,Thioredoxin reductase ,Helminthiasis ,Pharmaceutical Science ,Analytical Chemistry ,gold(I) complex ,Coordination Complexes ,Neoplasms ,Drug Discovery ,glutathione ,ComputingMilieux_MISCELLANEOUS ,anti-amoeba ,Anthelmintics ,0303 health sciences ,biology ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Pharmacology. Therapy ,auranofin ,anti-leishmanial ,3. Good health ,Chemistry ,Chemistry (miscellaneous) ,anti-helminth ,Human parasite ,Molecular Medicine ,Thioredoxin ,medicine.drug ,Auranofin ,antiparasitic ,Antiparasitic ,medicine.drug_class ,Antiprotozoal Agents ,Leishmania donovani ,Antineoplastic Agents ,anticancer ,Article ,Microbiology ,lcsh:QD241-441 ,03 medical and health sciences ,[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication ,lcsh:Organic chemistry ,Cell Line, Tumor ,redox equilibrium ,medicine ,Animals ,Humans ,[CHIM.COOR]Chemical Sciences/Coordination chemistry ,Physical and Theoretical Chemistry ,Amastigote ,Biology ,030304 developmental biology ,Protozoan Infections ,030306 microbiology ,Organic Chemistry ,thioredoxin ,biology.organism_classification ,Drug Evaluation ,Protozoa ,Cattle ,Gold - Abstract
Neglected parasitic diseases remain a major public health issue worldwide, especially in tropical and subtropical areas. Human parasite diversity is very large, ranging from protozoa to worms. In most cases, more effective and new drugs are urgently needed. Previous studies indicated that the gold(I) drug auranofin (Ridaura®, ) is effective against several parasites. Among new gold(I) complexes, the phosphole-containing gold(I) complex {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl (abbreviated as GoPI) is an irreversible inhibitor of both purified human glutathione and thioredoxin reductases. GoPI-sugar is a novel 1-thio-&beta, d-glucopyranose 2,3,4,6-tetraacetato-S-derivative that is a chimera of the structures of GoPI and auranofin, designed to improve stability and bioavailability of GoPI. These metal-ligand complexes are of particular interest because of their combined abilities to irreversibly target the essential dithiol/selenol catalytic pair of selenium-dependent thioredoxin reductase activity, and to kill cells from breast and brain tumors. In this work, screening of various parasites&mdash, protozoans, trematodes, and nematodes&mdash, was undertaken to determine the in vitro killing activity of GoPI-sugar compared to auranofin. GoPI-sugar was found to efficiently kill intramacrophagic Leishmania donovani amastigotes and adult filarial and trematode worms.
- Published
- 2020
42. Genome-wide analysis of blood lipid metabolites in over 5,000 South Asians reveals biological insights at cardiometabolic disease loci
- Author
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Unzila Ishtiaq, Dirk S. Paul, Zoubia Hina, Philippe M. Frossard, Danish Saleheen, Eric B. Fauman, Syed Nadeem Hasan Rizvi, Rachel M. Y. Ong, Nadeem Hayat Mallick, Syed Zahed Rasheed, Eric L. Harshfield, Angela M. Wood, Taniya Sattar, John Danesh, Fazal-ur-Rehman Memon, David Stacey, Shahid Abbas, Zameer-ul-Asar, Anis Memon, Zia Yaqub, Imran Saleem, Asif Rasheed, Albert Koulman, Anjum Jalal, M. Ishaq, Tahir Saghir, Adam S. Butterworth, Daniel Ziemek, Julian L. Griffin, and Nadeem Qamar
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Genetics ,education.field_of_study ,South asia ,Population ,Lipidomics ,Blood lipids ,Disease ,Lipidome ,Biology ,education ,Gene ,Genetic architecture - Abstract
BackgroundGenetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.MethodsWe characterised the genetic architecture of the human blood lipidome in 5,662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.ResultsWe identified 359 genetic associations with 255 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 616 genetic associations with 326 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.ConclusionsOur findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.
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- 2020
43. Biallelic variants in gle1 with survival beyond neonatal period
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Jamal Ghoumid, Sami Albaba, Martin Jakob Larsen, Maria Kibaek, Jens Michael Hertz, Thomas Smol, Philippe M. Campeau, Meena Balasubramanian, T. Michael Yates, University of Edinburgh, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute of Forensic Medicine [Odense], University of Southern Denmark (SDU), and Sheffield Children's NHS Foundation Trust
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Arthrogryposis ,0303 health sciences ,Nucleocytoplasmic Transport Proteins ,business.industry ,Period (gene) ,[SDV]Life Sciences [q-bio] ,030305 genetics & heredity ,Infant, Newborn ,Biology ,03 medical and health sciences ,Text mining ,Genetics ,Humans ,Genetic Predisposition to Disease ,Motor Neuron Disease ,business ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Demography - Abstract
International audience
- Published
- 2020
44. Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome
- Author
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David A. Stevenson, Karen Stals, Andrea Hanson-Kahn, Sian Ellard, Michael Bruccoleri, Clare E. Beesley, Emma Wakeling, Xiang-Jiao Yang, Matthew Wakeling, Sarah H. Elsea, Philippe M. Campeau, Angela Barnicoat, Meriel McEntagart, Richard Caswell, Charles Shaw-Smith, and Mary K. Kukolich
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Genetics ,gain-of-function ,biology ,Regulatory site ,Histone deacetylase 4 ,QH426-470 ,Chromosome 2q37 Deletion Syndrome ,HDAC4 ,Phenotype ,Article ,Chromatin ,Histone ,intellectual disability ,14-3-3 binding ,biology.protein ,Molecular Medicine ,Missense mutation ,Binding site ,Genetics (clinical) - Abstract
Summary Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder., Loss-of-function variants in histone deacetylase 4 (HDAC4) have been reported to cause brachydactyly-mental retardation (BDMR) syndrome through haploinsufficiency. This report describes 7 individuals with a phenotype distinct from BDMR, all with missense variants in a conserved 14-3-3 site, which are hypothesized to result in a novel gain-of-function effect in HDAC4.
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- 2020
45. Chitosan Contribution to Therapeutic and Vaccinal Approaches for the Control of Leishmaniasis
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Sébastien Pomel, Philippe M. Loiseau, and Simon L. Croft
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Antimony ,Paromomycin ,Polymers ,Pharmaceutical Science ,Biocompatible Materials ,02 engineering and technology ,Review ,Pharmacology ,chemotherapy ,Analytical Chemistry ,Chitosan ,chemistry.chemical_compound ,vaccine ,Drug Discovery ,media_common ,Titanium ,0303 health sciences ,biology ,Hydrogen-Ion Concentration ,drug carriers ,021001 nanoscience & nanotechnology ,Chemistry (miscellaneous) ,Molecular Medicine ,Rifampin ,0210 nano-technology ,Drug carrier ,Pentacyclic Triterpenes ,Drug ,Biocompatible polymers ,Curcumin ,media_common.quotation_subject ,Drug Compounding ,Antiprotozoal Agents ,macromolecular substances ,lcsh:QD241-441 ,03 medical and health sciences ,Selenium ,Pharmaceutical technology ,Cutaneous leishmaniasis ,lcsh:Organic chemistry ,Amphotericin B ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Betulinic Acid ,Leishmaniasis Vaccines ,leishmaniasis ,030304 developmental biology ,Thiomalates ,Macrophages ,Organic Chemistry ,technology, industry, and agriculture ,Leishmaniasis ,medicine.disease ,Leishmania ,biology.organism_classification ,Triterpenes ,carbohydrates (lipids) ,chemistry ,Nanoparticles ,chitosan - Abstract
The control of leishmaniases, a complex parasitic disease caused by the protozoan parasite Leishmania, requires continuous innovation at the therapeutic and vaccination levels. Chitosan is a biocompatible polymer administrable via different routes and possessing numerous qualities to be used in the antileishmanial strategies. This review presents recent progress in chitosan research for antileishmanial applications. First data on the mechanism of action of chitosan revealed an optimal in vitro intrinsic activity at acidic pH, high-molecular-weight chitosan being the most efficient form, with an uptake by pinocytosis and an accumulation in the parasitophorous vacuole of Leishmania-infected macrophages. In addition, the immunomodulatory effect of chitosan is an added value both for the treatment of leishmaniasis and the development of innovative vaccines. The advances in chitosan chemistry allows pharmacomodulation on amine groups opening various opportunities for new polymers of different size, and physico-chemical properties adapted to the chosen routes of administration. Different formulations have been studied in experimental leishmaniasis models to cure visceral and cutaneous leishmaniasis, and chitosan can act as a booster through drug combinations with classical drugs, such as amphotericin B. The various architectural possibilities given by chitosan chemistry and pharmaceutical technology pave the way for promising further developments.
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- 2020
46. PIGF deficiency causes a phenotype overlapping with DOORS syndrome
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Taroh Kinoshita, Thi Tuyet Mai Nguyen, Têmis Maria Félix, Fiona Stewart, Smrithi Salian, Yoshiko Murakami, Hind Benkerroum, Sanjay M. Sisodiya, Sheela Nampoothiri, and Philippe M. Campeau
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Male ,Adolescent ,Glycosylphosphatidylinositols ,Hearing Loss, Sensorineural ,Mutation, Missense ,Gene Expression ,Nails, Malformed ,Consanguinity ,Biology ,Craniofacial Abnormalities ,03 medical and health sciences ,DOOR syndrome ,Seizures ,Intellectual Disability ,Intellectual disability ,Exome Sequencing ,Genetics ,medicine ,Missense mutation ,Animals ,Humans ,Osteodystrophy ,Amino Acid Sequence ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,0303 health sciences ,030305 genetics & heredity ,Homozygote ,Infant ,Membrane Proteins ,medicine.disease ,Human genetics ,HEK293 Cells ,PIGF ,Female ,Hand Deformities, Congenital ,Sequence Alignment - Abstract
DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. In this study, we report two unrelated individuals with DOORS syndrome without deafness. Exome sequencing revealed a homozygous missense variant in PIGF (NM_173074.3:c.515C>G, p.Pro172Arg) in both. We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis through flow cytometry analysis. We thus describe the causal role of a novel disease gene, PIGF, in DOORS syndrome and highlight the overlap between this condition and GPI deficiency disorders. For each gene implicated in DOORS syndrome and/or inherited GPI deficiencies, there is considerable clinical variability so a high index of suspicion is warranted even though not all features are noted.
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- 2020
47. New Insights Into DNA Repair Revealed by NucS Endonucleases From Hyperthermophilic Archaea
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Likui Zhang, Donghao Jiang, Mai Wu, Zhihui Yang, Philippe M. Oger, Yangzhou University, Agricultural University of Hebei, Microbiologie, adaptation et pathogénie (MAP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Microbiology of Extreme Environments (M2E), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, and Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon)
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Microbiology (medical) ,Mutation rate ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,DNA repair ,DNA damage ,[SDV]Life Sciences [q-bio] ,Mini Review ,hyperthermophilic Archaea ,deaminated DNA repair ,lcsh:QR1-502 ,Microbiology ,Genome ,lcsh:Microbiology ,03 medical and health sciences ,Endonuclease ,chemistry.chemical_compound ,030304 developmental biology ,Genetics ,0303 health sciences ,biology ,030306 microbiology ,nucleotide excision repair ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,mismatch repair ,NucS endonuclease ,chemistry ,biology.protein ,DNA mismatch repair ,DNA ,Nucleotide excision repair - Abstract
International audience; Hyperthermophilic Archaea (HA) thrive in high temperature environments and their genome is facing severe stability challenge due to the increased DNA damage levels caused by high temperature. Surprisingly, HA display spontaneous mutation frequencies similar to mesophilic microorganisms, thereby indicating that the former must possess more efficient DNA repair systems than the latter to counteract the potentially enhanced mutation rates under the harsher environment. Although a few repair proteins or enzymes from HA have been biochemically and structurally characterized, the molecular mechanisms of DNA repair of HA remain largely unknown. Genomic analyses of HA revealed that they lack MutS/MutL homologues of the mismatch repair (MMR) pathway and the recognition proteins of the nucleotide excision repair (NER) pathway. Endonucleases play an essential role in DNA repair. NucS endonuclease, a novel endonuclease recently identified in some HA and bacteria, has been shown to act on branched, mismatched, and deaminated DNA, suggesting that this endonuclease is a multifunctional enzyme involved in NER, MMR, and deaminated base repair in a non-canonical manner. However, the catalytic mechanism and the physiological function of NucS endonucleases from HA need to be further clarified to determine how they participate in the different DNA repair pathways in cells from HA. In this review, we focus on recent advances in our understanding of the function of NucS endonucleases from HA in NER, MMR, and deaminated DNA repair, and propose directions for future studies of the NucS family of endonucleases.
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- 2020
48. Disrupted minor intron splicing is prevalent in Mendelian disorders
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Philippe M. Campeau, Anouk M. Olthof, Rahul N. Kanadia, and Jeffrey S. Rasmussen
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0301 basic medicine ,Spliceosome ,lcsh:QH426-470 ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,Gene Frequency ,Minor spliceosome ,Gene expression ,Genetics ,Humans ,splice ,Molecular Biology ,Gene ,Genetics (clinical) ,disease ,nervous system ,Alternative splicing ,Genetic Diseases, Inborn ,Intron ,Original Articles ,splice site ,Introns ,minor spliceosome ,Alternative Splicing ,lcsh:Genetics ,030104 developmental biology ,variant ,RNA splicing ,Original Article ,RNA Splice Sites - Abstract
Background Splicing is crucial for proper gene expression, and is predominately executed by the major spliceosome. Conversely, 722 introns in 699 human minor intron‐containing genes (MIGs) are spliced by the minor spliceosome. Splicing of these minor introns is disrupted in diseases caused by pathogenic variants in the minor spliceosome, ultimately leading to the aberrant expression of a subset of these MIGs. However, the effect of variants in minor introns and MIGs on diseases remains unexplored. Methods Variants in MIGs and associated clinical manifestations were identified using ClinVar. The HPO database was then used to curate the related symptoms and affected organ systems. Results: We found pathogenic variants in 211 MIGs, which commonly resulted in intellectual disability, seizures and microcephaly. This revealed a subset of MIGs whose aberrant splicing may contribute to the pathogenesis of minor spliceosome‐related diseases. Moreover, we identified 51 pathogenic variants in minor intron splice sites that reduce the splice site strength and can induce alternative splicing. Conclusion These findings highlight that disrupted minor intron splicing has a broader impact on human diseases than previously appreciated. The hope is that this knowledge will aid in the development of therapeutic strategies that incorporate the minor intron splicing pathway., Pathogenic variants in minor spliceosome components result in disrupted splicing of minor introns and a wide range of symptoms affecting many organ systems. Here, we identified a subset of minor intron‐containing genes that may play a role in the pathogenesis of these minor spliceosome‐related diseases. Moreover, we report the presence of 51 pathogenic variants in minor intron splice sites that result in a reduced splice site strength.
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- 2020
49. The minor and major spliceosome interact to regulate alternative splicing around minor introns
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Madisen F. Lee, Rahul N. Kanadia, Philippe M. Campeau, Cinzia Magnani, Alisa K. White, Alice Abdel Aleem, Almahdi Chakroun, Anouk M. Olthof, and Justine Rousseau
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Gene isoform ,Spliceosome ,medicine.anatomical_structure ,Minor spliceosome ,Polysome ,Alternative splicing ,medicine ,Intron ,Biology ,Gene ,Radial glial cell ,Cell biology - Abstract
Mutations in minor spliceosome components are linked to diseases such as Roifman syndrome, Lowry-Wood syndrome, and early-onset cerebellar ataxia (EOCA). Here we report that besides increased minor intron retention, Roifman syndrome and EOCA can also be characterized by elevated alternative splicing (AS) around minor introns. Consistent with the idea that the assembly/activity of the minor spliceosome informs AS in minor intron-containing genes (MIGs), inhibition of all minor spliceosome snRNAs led to upregulated AS. Notably, alternatively spliced MIG isoforms were bound to polysomes in the U11-null dorsal telencephalon, which suggested that aberrant MIG protein expression could contribute to disease pathogenesis. In agreement, expression of an aberrant isoform of the MIG Dctn3 by in utero electroporation, affected radial glial cell divisions. Finally, we show that AS around minor introns is executed by the major spliceosome and is regulated by U11-59K of the minor spliceosome, which forms exon-bridging interactions with proteins of the major spliceosome. Overall, we extend the exon-definition model to MIGs and postulate that disruptions of exon-bridging interactions might contribute to disease severity and pathogenesis.
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- 2020
50. Juvenile Paget’s Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor Sp7)
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Nori Kurihara, Homer Sedighi, Steven Mumm, Michael P. Whyte, William H. McAlister, Deborah J. Veis, G. David Roodman, Vinieth N. Bijanki, Philippe M. Campeau, Angela Nenninger, Gary S. Gottesman, and Shenghui Duan
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0301 basic medicine ,musculoskeletal diseases ,medicine.medical_specialty ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Article ,Bone remodeling ,03 medical and health sciences ,Osteosclerosis ,Young Adult ,0302 clinical medicine ,Osteoprotegerin ,Osteoclast ,Internal medicine ,Gene duplication ,Medicine ,Missense mutation ,Humans ,Sequence Deletion ,biology ,business.industry ,Homozygote ,RANK Ligand ,Osteoblast ,medicine.disease ,Osteitis Deformans ,3. Good health ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,RANKL ,Sp7 Transcription Factor ,Child, Preschool ,Mutation ,biology.protein ,Female ,business ,Transcription Factors - Abstract
Juvenile Paget's disease (JPD) became in 1974 the commonly used name for ultra-rare heritable occurrences of rapid bone remodeling throughout of the skeleton that present in infancy or early childhood as fractures and deformity hallmarked biochemically by marked elevation of serum alkaline phosphatase (ALP) activity (hyperphosphatasemia). Untreated, JPD can kill during childhood or young adult life. In 2002, we reported that homozygous deletion of the gene called tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B) encoding osteoprotegerin (OPG) explained JPD in Navajos. Soon after, other bi-allelic loss-of-function TNFRSF11B defects were identified in JPD worldwide. OPG inhibits osteoclastogenesis and osteoclast activity by decoying receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) away from its receptor RANK. Then, in 2014, we reported JPD in a Bolivian girl caused by a heterozygous activating duplication within TNFRSF11A encoding RANK. Herein, we identify mutation of a third gene underlying JPD. An infant girl began atraumatic fracturing of her lower extremity long-bones. Skull deformity and mild hearing loss followed. Our single investigation of the patient, when she was 15 years-of-age, showed generalized osteosclerosis and hyperostosis. DXA revealed a Z-score of +5.1 at her lumbar spine and T-score of +3.3 at her non-dominant wrist. Biochemical studies were consistent with positive mineral balance and several markers of bone turnover were elevated and included striking hyperphosphatasemia. Iliac crest histopathology was consistent with rapid skeletal remodeling. Measles virus transcripts, common in classic Paget's disease of bone, were not detected in circulating mononuclear cells. Then, reportedly, she responded to several months of alendronate therapy with less skeletal pain and correction of hyperphosphatasemia but had been lost to our follow-up. After we detected no defect in TNFRSF11A or B, trio exome sequencing revealed a de novo heterozygous missense mutation (c.926C>G; p.S309W) within SP7 encoding the osteoblast transcription factor osterix (specificity protein 7, transcription factor SP7). Thus, mutation of SP7 represents a third genetic cause of JPD.
- Published
- 2020
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