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1. Neuronal intranuclear inclusion disease is genetically heterogeneous

Author

Zhongbo Chen, Wai Yan Yau, Zane Jaunmuktane, Arianna Tucci, Prasanth Sivakumar, Sarah A. Gagliano Taliun, Chris Turner, Stephanie Efthymiou, Kristina Ibáñez, Roisin Sullivan, Farah Bibi, Alkyoni Athanasiou‐Fragkouli, Thomas Bourinaris, David Zhang, Tamas Revesz, Tammaryn Lashley, Michael DeTure, Dennis W. Dickson, Keith A. Josephs, Ellen Gelpi, Gabor G. Kovacs, Glenda Halliday, Dominic B. Rowe, Ian Blair, Pentti J. Tienari, Anu Suomalainen, Nick C. Fox, Nicholas W. Wood, Andrew J. Lees, Matti J. Haltia, Genomics England Research Consortium, John Hardy, Mina Ryten, Jana Vandrovcova, and Henry Houlden

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico‐based screening using whole‐genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.

Published
2020
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2. Genome‐Wide Association Study Identifies Risk Loci for Cluster Headache

Author

Elisabet Waldenlind, Lou Grangeon, Nicholas W. Wood, Benjamin S. Simpson, Susie Lagrata, Laura Southgate, Aster V.E. Harder, Franziska Liesecke, Roisin Sullivan, Jana Vandrovcova, M. Zameel Cader, Prasanth Sivakumar, Carmen Fourier, Ingrid Kockum, Lisanne S. Vijfhuizen, Michail Vikelis, Janice Yip, Bendik S. Winsvold, Emer O'Connor, Joycee Adebimpe, Henry Houlden, Olivia Quinn, Richard C. Trembath, Koen Paemeleire, Stephanie Efthymiou, Manjit Matharu, Tim Kelderman, Caroline Ran, Fayyaz Ahmed, Nicola Giffin, Daisuke Danno, Christina Sjöstrand, Nicholas Silver, Andrea Carmine Belin, Isabel C Hostettler, Emer Kilbride, Anna Steinberg, Gianpiero L. Cavalleri, Brendan Davies, and Ciaran Campbell

Subjects
Male, EXPRESSION, PATHOPHYSIOLOGY, Cluster Headache, VERAPAMIL, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Cohort Studies, MICROGLIA, Medicine and Health Sciences, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, METAANALYSIS, Sweden, Genetics, Cluster headache, Odds ratio, medicine.disease, GENE, United Kingdom, Neurology, Migraine, Genetic Loci, Case-Control Studies, Female, Neurology (clinical), Imputation (genetics), Genome-Wide Association Study
Abstract

OBJECTIVE This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

Published
2021

3. A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Author

de Boer, Elke, Ockeloen, Charlotte W., Matalonga, Leslie, Horvath, Rita, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Gilissen, Christian, Johari, Mridul, Laurie, Steven, Li, Shuang, Nelson, Isabelle, Peters, Sophia, Paramonov, Ida, Prasanth, Sivakumar, Robinson, Peter, Sablauskas, Karolis, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vitobello, Antonio, Rodenburg, Richard J., Coenen, Marieke J. H., Janssen, Mirian, Henssen, Dylan, Banka, Siddharth, Benetti, Elisa, Casari, Giorgio, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Ellwanger, Kornelia, Faivre, Laurence, Graessner, Holm, Haack, Tobias B., Hammarsjö, Anna, Havlovicova, Marketa, Hoischen, Alexander, Hugon, Anne, Jackson, Adam, Kleefstra, Tjitske, Lindstrand, Anna, López-Martín, Estrella, Macek, Milan, Morleo, Manuela, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca Clementina, Renieri, Alessandra, Rooryck, Caroline, Ryba, Lukas, Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Verloes, Alain, Vissers, Lisenka, Votypka, Pavel, Vyshka, Klea, Zurek, Birte, Trimouille, Aurélien, Vissers, Lisenka E. L. M., Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Research Council, Evelyn Trust, Newton Fund, European Project: 825619,AI4EU, Dutch Research Council (Holanda), Medical Research Council (Reino Unido), Lily Foundation, Unión Europea. Comisión Europea. H2020, Ockeloen, Charlotte W [0000-0003-0329-1520], Horvath, Rita [0000-0002-9841-170X], Rodenburg, Richard J [0000-0001-5227-3527], Gilissen, Christian [0000-0003-1693-9699], Steyaert, Wouter [0000-0001-8393-0788], Trimouille, Aurélien [0000-0002-3457-5684], Verloes, Alain [0000-0003-4819-0264], Vissers, Lisenka ELM [0000-0001-6470-5497], Apollo - University of Cambridge Repository, de Boer, E., Ockeloen, C. W., Matalonga, L., Horvath, R., Rodenburg, R. J., Coenen, M. J. H., Janssen, M., Henssen, D., Gilissen, C., Steyaert, W., Paramonov, I., Trimouille, A., Kleefstra, T., Verloes, A., Vissers, L. E. L. M., Nigro, V., Torella, A., and Banfi, S.

Subjects
Male, Proband, Mitochondrial DNA, RNA, Transfer, Leu, Brief Communication, Quadriplegia, Whole Exome Sequencing, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Young Adult, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual Disability, Exome Sequencing, Genetics research, Intellectual disability, Genetics, medicine, Humans, Genetics (clinical), Exome sequencing, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Neurodevelopmental disorders, 030305 genetics & heredity, Correction, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Translational research, medicine.disease, Heteroplasmy, 3. Good health, MT-TL1, Mutation, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Spastic tetraparesis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Neurological disorders, 030217 neurology & neurosurgery
Abstract

Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis. Eur J Hum Genet. 2021 Sep;29(9):1470-1471. doi: 10.1038/s41431-021-00937-3. The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to TK and 015.014.066 to LELMV), the European Research Council (ERC to RH), the Well come Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH), and the Evelyn Trust (RH). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257. Sí

Published
2021

4. Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

Author

Prasanth Sivakumar, Jack Humphrey, Keith A. Josephs, Mercedes Prudencio, E. Aubrey Thompson, Kevin Talbot, Bjorn Oskarsson, Hemali Phatnani, Leonard Petrucelli, Ana Candalija, David S. Knopman, Pietro Fratta, Casey Cook, Yari Carlomagno, Cristhoper H. Fernandez De Castro, Duyang Kim, Neil Graff-Radford, Maria Secrier, Siddharthan Chandran, Mei Yue, Anna-Leigh Brown, Sarah E. Hill, Bhuvaneish T. Selvaraj, Michael G. Heckman, Cristian Bodo, Karen Jansen-West, Michael E. Ward, Demetra Catalano, Samantha Fennessey, Elizabeth M. C. Fisher, Michael DeTure, Ronald C. Petersen, Dennis W. Dickson, Jia Newcombe, Isabel Hubbard, Delphine Fagegaltier, Tania F. Gendron, Ying-Chih Wang, Karen Burr, Lillian M. Daughrity, Tammaryn Lashley, J. Shi, Yuping Song, Jennifer M. Kachergus, Matthew R. Spiegel, Rosa Rademakers, Marka van Blitterswijk, Shunsuke Koga, Bradley F. Boeve, Sarah R. Pickles, Nadia Propp, and Towfique Raj

Subjects
Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Induced Pluripotent Stem Cells, Stathmin, Disease, TARDBP, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Humans, Medicine, Dementia, biology, business.industry, nutritional and metabolic diseases, RNA, General Medicine, Human brain, Middle Aged, medicine.disease, Frontal Lobe, nervous system diseases, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, Frontotemporal Dementia, 030220 oncology & carcinogenesis, Mutation, Commentary, biology.protein, Female, business, Biomarkers, Frontotemporal dementia
Abstract

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

Published
2020

5. Neuronal intranuclear inclusion disease is genetically heterogeneous

Author

Gabor G. Kovacs, Tammaryn Lashley, Sarah A Gagliano Taliun, Zhongbo Chen, Glenda M. Halliday, Ellen Gelpi, Dennis W. Dickson, Matti Haltia, Roisin Sullivan, Henry Houlden, Thomas Bourinaris, Dominic B. Rowe, Arianna Tucci, Ian P. Blair, Stephanie Efthymiou, Wai Yan Yau, Prasanth Sivakumar, John Hardy, Anu Suomalainen, Kristina Ibáñez, Farah Bibi, Michael DeTure, Pentti J. Tienari, Zane Jaunmuktane, David Zhang, Chris Turner, Nicholas W. Wood, Andrew J. Lees, Alkyoni Athanasiou-Fragkouli, Mina Ryten, Nick C. Fox, Keith A. Josephs, Jana Vandrovcova, Tamas Revesz, HUS Neurocenter, Department of Neurosciences, Clinicum, Neurologian yksikkö, TRIMM - Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, HUSLAB, STEMM - Stem Cells and Metabolism Research Program, Anu Wartiovaara / Principal Investigator, Research Programs Unit, Neuroscience Center, Helsinki Institute of Life Science HiLIFE, Medicum, and Department of Pathology

Subjects
0301 basic medicine, Eosinophilic inclusions, In silico, Neurosciences. Biological psychiatry. Neuropsychiatry, Disease, Brief Communication, Genome, 3124 Neurology and psychiatry, 03 medical and health sciences, NEURONAL INTRANUCLEAR INCLUSION DISEASE, REPEAT, 0302 clinical medicine, Medicine, BODY, RC346-429, Genetics, Genetic heterogeneity, business.industry, General Neuroscience, Haplotype, 3112 Neurosciences, 3. Good health, 030104 developmental biology, Neurology. Diseases of the nervous system, Neurology (clinical), Brief Communications, Trinucleotide repeat expansion, business, 030217 neurology & neurosurgery, RC321-571
Abstract

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion inNOTCH2NLCwas recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico-based screening using whole-genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.

Published
2020

6. Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Author

Matalonga, Leslie, Hernández-Ferrer, Carles, DITF-ITHACA, Solve-RD, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Vyshka, Klea, Zurek, Birte, Baets, Jonathan, Beijer, Danique, Bonne, Gisèle, Cohen, Enzo, DITF-euroNMD, Solve-RD, Cossins, Judith, Evangelista, Teresinha, Ferlini, Alessandra, Hackman, Peter, Hanna, Michael G, Horvath, Rita, Houlden, Henry, Johari, Mridul, Lau, Jarred, Lochmüller, Hanns, DITF-RND, Solve-RD, Macken, William L, Musacchia, Francesco, Nascimento, Andres, Natera-de Benito, Daniel, Nigro, Vincenzo, Piluso, Giulio, Pini, Veronica, Pitceathly, Robert D S, Polavarapu, Kiran, Cruz, Pedro M Rodriguez, Tonda, Raul, Sarkozy, Anna, Savarese, Marco, Selvatici, Rita, Thompson, Rachel, Udd, Bjarne, Van de Vondel, Liedewei, Vandrovcova, Jana, Zaharieva, Irina, Balicza, Peter, Laurie, Steven, Chinnery, Patrick, Dürr, Alexandra, Haack, Tobias, Hengel, Holger, Kamsteeg, Erik-Jan, Kamsteeg, Christoph, Lohmann, Katja, Macaya, Alfons, Marcé-Grau, Anna, Fernandez-Callejo, Marcos, Maver, Ales, Molnar, Judit, Münchau, Alexander, Peterlin, Borut, Riess, Olaf, Schöls, Ludger, Schüle-Freyer, Rebecca, Stevanin, Giovanni, Synofzik, Matthis, Timmerman, Vincent, Picó, Daniel, van de Warrenburg, Bart, van Os, Nienke, Wayand, Melanie, Wilke, Carlo, Haack, Tobias B, Graessner, Holm, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Garcia-Linares, Carles, Sturm, Marc, Schulze-Hentrich, Julia M, Kessler, Christoph, Heutink, Peter, Brunner, Han, Scheffer, Hans, Papakonstantinou, Anastasios, Hoogerbrugge, Nicoline, 't Hoen, Peter A C, Steyaert, Wouter, Sablauskas, Karolis, Te Paske, Iris, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Corvó, Alberto, Brookes, Anthony J, Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Piscia, Davide, Joshi, Ricky, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Duffourd, Yannis, Tisserant, Emilie, Diez, Hector, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Bullich, Gemma, Gut, Ivo, Corvo, Alberto, Garcia, Carles, Hernández, Carles, Paramonov, Ida, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hoischen, Alexander, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Consortia, Solve-RD, Spalding, Dylan, Senf, Alexander, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Reilly, Mary, Muntoni, Francesco, de Jonghe, Peter, Banfi, Sandro, Torella, Annalaura, Cuesta, Isabel, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A, Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B, group, Solve-RD SNV-indel working, Denommé-Pichon, Anne-Sophie, Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F Javier Alonso García, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Molnar, Maria Judit, Gilissen, Christian, Herzog, Rebecca, Pauly, Martje, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Beeson, David, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Li, Shuang, Prasanth, Sivakumar, Robinson, Peter, van der Velde, Joeri K, de Voer, Richarda M, Evans, Gareth, Sommer, Anna Katharina, Töpf, Ana, Paske, Iris Te, Tischkowitz, Marc, Casari, Giorgio, Ciolfi, Andrea, Dallapiccola, Bruno, de Boer, Elke, Vissers, Lisenka E L M, Hammarsjö, Anna, Havlovicova, Marketa, Hugon, Anne, de Voer, Richarda, Kleefstra, Tjitske, Lindstrand, Anna, López-Martín, Estrella, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, DITF-GENTURIS, Solve-RD, Posada, Manuel, Ryba, Lukas, Schwarz, Martin, Trimouille, Aurélien, Solve RD SNV Indel Working Grp, Solve RD DITF GENTURIS, Solve RD DITF ITHACA, Solve RD DITF-euroNMD, Solve RD DITF RND, Solve RD Consortia, Matalonga, L., Hernandez-Ferrer, C., Piscia, D., Cohen, E., Cuesta, I., Danis, D., Denomme-Pichon, A. -S., Duffourd, Y., Gilissen, C., Johari, M., Laurie, S., Li, S., Nelson, I., Peters, S., Paramonov, I., Prasanth, S., Robinson, P., Sablauskas, K., Savarese, M., Steyaert, W., van der Velde, J. K., Vitobello, A., Schule, R., Synofzik, M., Topf, A., Vissers, L. E. L. M., de Voer, R., Aretz, S., Capella, G., de Voer, R. M., Evans, G., Pelaez, J. G., Holinski-Feder, E., Hoogerbrugge, N., Laner, A., Oliveira, C., Rump, A., Schrock, E., Sommer, A. K., Steinke-Lange, V., Paske, I., Tischkowitz, M., Valle, L., Banka, S., Benetti, E., Casari, G., Ciolfi, A., Clayton-Smith, J., Dallapiccola, B., de Boer, E., Ellwanger, K., Faivre, L., Graessner, H., Haack, T. B., Hammarsjo, A., Havlovicova, M., Hoischen, A., Hugon, A., Jackson, A., Kleefstra, T., Lindstrand, A., Lopez-Martin, E., Macek, M., Morleo, M., Nigro, V., Nordgren, A., Pettersson, M., Pinelli, M., Pizzi, S., Posada, M., Radio, F. C., Renieri, A., Rooryck, C., Ryba, L., Schwarz, M., Tartaglia, M., Thauvin, C., Torella, A., Trimouille, A., Verloes, A., Vissers, L., Votypka, P., Vyshka, K., Zurek, B., Baets, J., Beijer, D., Bonne, G., Cossins, J., Evangelista, T., Ferlini, A., Hackman, P., Hanna, M. G., Horvath, R., Houlden, H., Lau, J., Lochmuller, H., Macken, W. L., Musacchia, F., Nascimento, A., Natera-de Benito, D., Piluso, G., Pini, V., Pitceathly, R. D. S., Polavarapu, K., Cruz, P. M. R., Sarkozy, A., Selvatici, R., Thompson, R., Udd, B., Van de Vondel, L., Vandrovcova, J., Zaharieva, I., Balicza, P., Chinnery, P., Durr, A., Haack, T., Hengel, H., Kamsteeg, E. -J., Kamsteeg, C., Lohmann, K., Macaya, A., Marce-Grau, A., Maver, A., Molnar, J., Munchau, A., Peterlin, B., Riess, O., Schols, L., Schule-Freyer, R., Stevanin, G., Timmerman, V., van de Warrenburg, B., van Os, N., Wayand, M., Wilke, C., Tonda, R., Fernandez-Callejo, M., Pico, D., Garcia-Linares, C., Papakonstantinou, A., Corvo, A., Joshi, R., Diez, H., Gut, I., Beltran, S., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Kessler, C., Heutink, P., Brunner, H., Scheffer, H., 't Hoen, P. A. C., te Paske, I., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Specht, S., Alexander, E., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Bullich, G., Garcia, C., Hernandez, C., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Allamand, V., Yaou, R. B., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Kremlik, V., Parkinson, H., Keane, T., Spalding, D., Senf, A., Robert, G., Costa, A., Patch, C., Hanna, M., Reilly, M., Muntoni, F., de Jonghe, P., Banfi, S., Rossi, R., Neri, M., Spier, I., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Castello, R., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Molnar, M. J., Herzog, R., Pauly, M., Osorio, A. N., de Benito, D. N., Beeson, D., Unión Europea. Comisión Europea. H2020, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), Government of Catalonia (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto Nacional de Bioinformatica (España), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Instituto de Salud Carlos III [Madrid] (ISC), Radboud University Medical Center [Nijmegen], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Barcelona Institute of Science and Technology (BIST), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Folkhälsan Research Center, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Myologie, University of Helsinki, Department of Medical and Clinical Genetics, Medicum, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Genetic testing, Computer science, genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], EXOME, MEDICAL GENETICS, Diseases, Disease, VARIANTS, Genome informatics, Genomic analysis, Diseases, Genetic testing, Genome informatics, Genomic analysis, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Exome, Genetics (clinical), Exome sequencing, 0303 health sciences, Application programming interface, methods [Genomics], 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Pedigree, diagnosis [Rare Diseases], Chemistry, Medical genetics, medicine.medical_specialty, methods [Genetic Testing], MEDLINE, Socio-culturale, Phenome, AMERICAN-COLLEGE, INHERITANCE, Sensitivity and Specificity, Article, standards [Genetic Testing], 03 medical and health sciences, Rare Diseases, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetics, medicine, Humans, ddc:610, Genetic Testing, Biology, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Data science, Workflow, 3111 Biomedicine, standards [Genomics], Human medicine, Software
Abstract

Correction to: Solving patients with rare diseases through programmatic reanalysis of genome-phenome data. Eur J Hum Genet. 2021 Sep;29(9):1466-1469. doi: 10.1038/s41431-021-00934-6. PMID: 34393220 Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. We also acknowledge the support of the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement and the Co-financing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program. Sí

Published
2021

7. Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

Author

Töpf, Ana, Pyle, Angela, Griffin, Helen, Matalonga, Leslie, Schon, Katherine, Sickmann, Albert, Schara–Schmidt, Ulrike, Hentschel, Andreas, Chinnery, Patrick F., Kölbel, Heike, Roos, Andreas, Horvath, Rita, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Gilissen, Christian, Johari, Mridul, Laurie, Steven, Li, Shuang, Nelson, Isabelle, Paramonov, Ida, Peters, Sophia, Prasanth, Sivakumar, Robinson, Peter, Sablauskas, Karolis, Savarese, Marco, Steyaert, Wouter, Van Der Velde, Joeri K., Vitobello, Antonio, Baets, Jonathan, Beijer, Danique, Bonne, Gisèle, Cossins, Judith, Evangelista, Teresinha, Ferlini, Alessandra, Hackman, Peter, Hanna, Michael G., Houlden, Henry, Lau, Jarred, Lochmüller, Hanns, Macken, William L., Musacchia, Francesco, Nascimento, Andres, Natera-De Benito, Daniel, Nigro, Vincenzo, Piluso, Giulio, Pini, Veronica, Pitceathly, Robert D. S., Polavarapu, Kiran, Cruz, Pedro M. Rodriguez, Sarkozy, Anna, Selvatici, Rita, Thompson, Rachel, Torella, Annalaura, Udd, Bjarne, Van De Vondel, Liedewei, Vandrovcova, Jana, Zaharieva, Irina, Schon, Katherine [0000-0001-8054-8954], Horvath, Rita [0000-0002-9841-170X], Apollo - University of Cambridge Repository, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Barcelona Institute of Science and Technology (BIST), University of Cambridge [UK] (CAM), Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Aberdeen, Ruhr-Universität Bochum [Bochum], University Children's Hospital of Essen [Essen, Germany], Enzo Cohen, Isabel Cuesta, Daniel Danis, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Christian Gilissen, Mridul Johari, Steven Laurie, Shuang Li, Isabelle Nelson, Ida Paramonov, Sophia Peters, Sivakumar Prasanth, Peter Robinson, Karolis Sablauskas, Marco Savarese, Wouter Steyaert, Joeri K van der Velde, Antonio Vitobello, Jonathan Baets, Danique Beijer, Gisèle Bonne, Judith Cossins, Teresinha Evangelista, Alessandra Ferlini, Peter Hackman, Michael G Hanna, Henry Houlden, Jarred Lau, Hanns Lochmüller, William L Macken, Francesco Musacchia, Andres Nascimento, Daniel Natera-de Benito, Vincenzo Nigro, Giulio Piluso, Veronica Pini, Robert D S Pitceathly, Kiran Polavarapu, Pedro M Rodriguez Cruz, Anna Sarkozy, Rita Selvatici, Rachel Thompson, Annalaura Torella, Bjarne Udd, Liedewei Van de Vondel, Jana Vandrovcova, Irina Zaharieva, Töpf, Ana, Pyle, Angela, Griffin, Helen, Matalonga, Leslie, Schon, Katherine, Sickmann, Albert, Schara-Schmidt, Ulrike, Hentschel, Andrea, Chinnery, Patrick F, Kölbel, Heike, Roos, Andrea, Horvath, Rita, Nigro, Vincenzo, Torella, Annalaura, and Piluso, Giulio

Subjects
0301 basic medicine, Male, Proteome, 45/41, Developmental Disabilities, Medizin, 45/22, Biology, Bioinformatics, Nervous System Malformations, Brief Communication, 82/80, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Cerebellum, 38/23, Genetics research, Genetics, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Exome, Genetic Testing, Gene, Cerebellar hypoplasia, Genetics (clinical), Exome sequencing, Proteomic Profile, Proteomic Profiling, 82/58, 631/208/514/2254, brief-communication, 692/308/2056, Infant, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Spinal muscular atrophy, medicine.disease, 3. Good health, 030104 developmental biology, Congenital muscular dystrophy, Next-generation sequencing, 030217 neurology & neurosurgery, Transcription Factors
Abstract

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient's fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Several authors of this study are members of the European Reference Network for Neuromuscular disease, Project ID No 739543. This study was supported by the AFM (grant 21644 to AR), the framework of the NME-GPS project by the European Regional Development Fund (AR/US/AS), the support by the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierende Bürgermeister von Berlin-inkl. Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung (AH and AS), the European Research Council (RH), the Wellcome Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH) and the Evelyn Trust (RH). This research was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1 and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care

Published
2020

8. Author Correction: Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia

Author

Adriana P. Rebelo, Wai Yan Yau, Jack Humphrey, Eloise Tribollet, Vincenzo Salpietro, Nicholas W. Wood, Henry Houlden, Roberto Simone, Elena Buglo, Stephan Züchner, Huma Tariq, Zane Jaunmuktane, Prasanth Sivakumar, Roisin Sullivan, Muhammad Ilyas, Wilson Marques, Mary M. Reilly, Pedro J. Tomaselli, Grazia Devigili, Adolfo M. Bronstein, James M. Polke, Stephanie Efthymiou, Pietro Fratta, Nadja S. Andrade, Ilaria Callegari, Maurizio Versino, Andrea Cortese, Diego Kaski, Jana Vandrovcova, and Alexander M. Rossor

Subjects
0303 health sciences, Pediatrics, medicine.medical_specialty, Neuromuscular disease, Movement disorders, Ataxia, Computer Science::Computation and Language (Computational Linguistics and Natural Language and Speech Processing), Late onset, Biology, medicine.disease, Article, 03 medical and health sciences, 0302 clinical medicine, Common cause and special cause, otorhinolaryngologic diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Genetics, medicine, medicine.symptom, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication facsstor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)(11) allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.

Published
2019

9. TDP-43 mutations increase HNRNP A1-7B through gain of splicing function

Author

Thomas J. Cunningham, Jack Humphrey, Prasanth Sivakumar, Francesca De Giorgio, Nicol Birsa, Pietro Fratta, Agnieszka M. Ule, Abraham Acevedo-Arozena, Elizabeth M. C. Fisher, Vincent Plagnol, Matthew Bentham, Remya R. Nair, and Jacob Neeves

Subjects
0301 basic medicine, Heterogeneous Nuclear Ribonucleoprotein A1, RNA Splicing, Amyotrophic Lateral Sclerosis, Biology, Cell biology, DNA-Binding Proteins, 03 medical and health sciences, Alternative Splicing, 030104 developmental biology, 0302 clinical medicine, RNA splicing, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Mutation, Humans, Neurology (clinical), Letters to the Editor, 030217 neurology & neurosurgery, Function (biology)
Published
2018

10. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia

Author

Nadja S. Andrade, Nicholas W. Wood, Stephan Züchner, Adriana P. Rebelo, Roisin Sullivan, Pietro Fratta, Grazia Devigili, Wai Yan Yau, Vincenzo Salpietro, Alexander M. Rossor, Jack Humphrey, Mary M. Reilly, Stephanie Efthymiou, Wilson Marques, Zane Jaunmuktane, Roberto Simone, Eloise Tribollet, Pedro J. Tomaselli, Ilaria Callegari, Huma Tariq, Muhammad Ilyas, James M. Polke, Adolfo M. Bronstein, Henry Houlden, Prasanth Sivakumar, Elena Buglo, Maurizio Versino, Andrea Cortese, Diego Kaski, and Jana Vandrovcova

Subjects
Adult, Male, Ataxia, Movement disorders, Cerebellar Ataxia, Biology, RFC1, Repetitive Sequences, otorhinolaryngologic diseases, Genetics, medicine, Humans, Allele, Replication Protein C, Loss function, Alleles, Aged, Repetitive Sequences, Nucleic Acid, Vestibular areflexia, Cerebellar ataxia, Nucleic Acid, Whole Genome Sequencing, Middle Aged, Introns, medicine.symptom, Trinucleotide repeat expansion
Abstract

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.

Published
2018

11. Mice with endogenous <scp>TDP</scp> ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

Author

David E. Housman, Prasanth Sivakumar, Martina Hallegger, Cristian Bodo, Bernadett Kalmar, Warren Emmett, Hugo Alexandre Mendes Oliveira, Philip Stanier, Adrian M. Isaacs, Alexander E. Conicella, Linda Greensmith, Lydia Teboul, Pietro Fratta, Alessandro Marrero-Gagliardi, Vincent Plagnol, Nicolas L. Fawzi, José M. Brito-Armas, Nicol Birsa, Yichao Yu, Erwin Pauws, Emma Peskett, Joffrey Mianné, Agnieszka M. Ule, Gemma F. Codner, T. Ricketts, Andrea Calvo, Silvia Corrochano, Toby Collins, Jack Humphrey, M Groves, Mark F. Lythgoe, Emanuele Buratti, Francisco E. Baralle, Eric T. Wang, Adriano Chiò, Alan Mejia Maza, Michelle Stewart, Yoichi Gondo, Ryutaro Fukumura, Kitty Lo, Elizabeth M. C. Fisher, Abraham Acevedo-Arozena, Massachusetts Institute of Technology. Department of Biology, Wang, Eric T, and Housman, David E

Subjects
Genetics and Molecular Biology (all), 0301 basic medicine, TDP-43, Immunology and Microbiology (all), RNA-binding protein, medicine.disease_cause, Biochemistry, Mice, Exon, 0302 clinical medicine, Molecular Biology of Disease, News & Views, Motor Neurons, Mutation, General Neuroscience, RNA-Binding Proteins, ALS, cryptic exon, skiptic exon, splicing, Neuroscience (all), Molecular Biology, Biochemistry, Genetics and Molecular Biology (all), Articles, Exons, RNA Biology, Cell biology, DNA-Binding Proteins, RNA splicing, RNA Splicing, Biology, TARDBP, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, mental disorders, medicine, Animals, Humans, Loss function, General Immunology and Microbiology, Point mutation, Amyotrophic Lateral Sclerosis, Alternative splicing, nutritional and metabolic diseases, nervous system diseases, TDP‐43, Alternative Splicing, 030104 developmental biology, Gene Expression Regulation, 030217 neurology & neurosurgery, Neuroscience
Abstract

TDP-43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects. TDP-43 gain-of-function effects in these mice reveal a novel category of splicing events controlled by TDP-43, referred to as "skiptic" exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain-of-function mutation in endogenous Tardbp causes an adult-onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain-of-function and skiptic exons in ALS patient-derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP-43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages. Keywords: ALS; cryptic exon; skiptic exon; splicing; TDP-43

Published
2018

12. Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice

Author

Anny, Devoy, Bernadett, Kalmar, Michelle, Stewart, Heesoon, Park, Beverley, Burke, Suzanna J, Noy, Yushi, Redhead, Jack, Humphrey, Kitty, Lo, Julian, Jaeger, Alan, Mejia Maza, Prasanth, Sivakumar, Cinzia, Bertolin, Gianni, Soraru, Vincent, Plagnol, Linda, Greensmith, Abraham, Acevedo Arozena, Adrian M, Isaacs, Benjamin, Davies, Pietro, Fratta, and Elizabeth M C, Fisher

Subjects
amyotrophic lateral sclerosis, frameshift mutation, RNA binding protein FUS, nerve degeneration, Gene Dosage, gene targeting, transcriptomics, Mice, antibody, mitochondrion, animal, genetics, proteinosis, Gene Knock-In Techniques, Frameshift Mutation, Neuromuscular Junction/metabolism, progressive motor neuron degeneration, motoneuron, Motor Neurons, epitope, neuromuscular junction, pathogenesis, Delta14, Amyotrophic Lateral Sclerosis/genetics, peptide, Mitochondria, female, priority journal, Endoplasmic Reticulum, Rough, Ribosomal Proteins, Heterozygote, humanization, animal experiment, Neuromuscular Junction, rough endoplasmic reticulum, Protein Aggregation, Pathological, Article, ribosome protein, male, Mitochondria/metabolism, gene expression profiling, heterozygosity, Animals, Humans, controlled study, mutant, human, mouse, FUS, nerve cell degeneration, nonhuman, Gene Expression Profiling, animal model, disease model, Amyotrophic Lateral Sclerosis, Endoplasmic Reticulum, Rough/metabolism, Protein Aggregation, Pathological/genetics, Disease Models, Animal, Ribosomal Proteins/genetics, RNA-Binding Protein FUS, ALS, RNA-Binding Protein FUS/genetics, metabolism, Motor Neurons/metabolism, Reports
Abstract

Devoy et al. develop the first mouse model to fully recapitulate human FUS-ALS, as defined by midlife-onset progressive degeneration of motor neurons with dominant inheritance. A toxic gain of function occurs in the absence of FUS protein aggregation, involving disturbance of ribosomes and mitochondria at the endoplasmic reticulum., Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease—with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.

Published
2017

13. Dissecting TDP-43 gain- and loss-of-function in neurodegeneration

Author

Abraham Acevedo Arozena, Pietro Fratta, Francisco E. Baralle, K. Lo, Bernadett Kalmar, Elizabeth M. C. Fisher, Jack Humphrey, T. Ricketts, Prasanth Sivakumar, Linda Greensmith, H. Oliveira, David E. Housman, Vincent Plagnol, Eric T. Wang, and Emanuele Buratti

Subjects
Neurology, Pediatrics, Perinatology and Child Health, Neurodegeneration, medicine, Neurology (clinical), Biology, medicine.disease, Neuroscience, Genetics (clinical), Loss function
Published
2018

14. Investigating dysfunctional RNA processing in TDP-43 mouse mutants

Author

Prasanth Sivakumar, Pietro Fratta, Cristian Bodo, Linda Greensmith, Jack Humphrey, Agnieszka M. Ule, T. Ricketts, H. Oliveira, Vincent Plagnol, Abraham Acevedo-Arozena, David E. Housman, Eric T. Wang, Warren Emmett, Elizabeth M. C. Fisher, Francisco E. Baralle, and Emanuele Buratti

Subjects
Genetics, Rna processing, Neurology, Pediatrics, Perinatology and Child Health, Mutant, Dysfunctional family, Neurology (clinical), Biology, Genetics (clinical)
Published
2017

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