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1. Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

Author

Chee, Justine M, Lanoue, Louise, Clary, Dave, Higgins, Kendall, Bower, Lynette, Flenniken, Ann, Guo, Ruolin, Adams, David J, Bosch, Fatima, Braun, Robert E, Brown, Steve DM, Chin, H-J Genie, Dickinson, Mary E, Hsu, Chih-Wei, Dobbie, Michael, Gao, Xiang, Galande, Sanjeev, Grobler, Anne, Heaney, Jason D, Herault, Yann, de Angelis, Martin Hrabe, Mammano, Fabio, Nutter, Lauryl MJ, Parkinson, Helen, Qin, Chuan, Shiroishi, Toshi, Sedlacek, Radislav, Seong, J-K, Xu, Ying, International Mouse Phenotyping Consortium, Brooks, Brian, McKerlie, Colin, Lloyd, KC Kent, Westerberg, Henrik, and Moshiri, Ala

Subjects
Mouse, Knockout, Embryonic Development, Eye, Mice, CPLANE, IMPC, MAC spectrum, Genetics, Animals, Humans, Microphthalmos, 2.1 Biological and endogenous factors, Eye Abnormalities, Aetiology, Eye Disease and Disorders of Vision, Mammals, Pediatric, Serine-glycine biosynthesis, Eye development, Human Genome, Anophthalmos, Biological Sciences, Coloboma, Phenotype, Congenital Structural Anomalies, International Mouse Phenotyping Consortium, Biotechnology, Developmental Biology
Abstract

BackgroundMicrophthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome.ResultsQuery of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation.ConclusionsUsing genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

Published
2023

2. Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes

Author

Higgins, Kendall, Moore, Bret A, Berberovic, Zorana, Adissu, Hibret A, Eskandarian, Mohammad, Flenniken, Ann M, Shao, Andy, Imai, Denise M, Clary, Dave, Lanoue, Louise, Newbigging, Susan, Nutter, Lauryl MJ, Adams, David J, Bosch, Fatima, Braun, Robert E, Brown, Steve DM, Dickinson, Mary E, Dobbie, Michael, Flicek, Paul, Gao, Xiang, Galande, Sanjeev, Grobler, Anne, Heaney, Jason D, Herault, Yann, de Angelis, Martin Hrabe, Chin, Hsian-Jean Genie, Mammano, Fabio, Qin, Chuan, Shiroishi, Toshihiko, Sedlacek, Radislav, Seong, J-K, Xu, Ying, IMPC Consortium, Lloyd, KC Kent, McKerlie, Colin, and Moshiri, Ala

Subjects
Knockout, Human Genome, Cell Cycle Proteins, Nerve Tissue Proteins, Ciliopathies, Mice, Databases, Gene Knockout Techniques, IMPC Consortium, Genetics, Animals, 2.1 Biological and endogenous factors, Cilia, Aetiology, Factual, Biotechnology
Abstract

We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of "candidate ciliopathy genes." From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.

Published
2022

3. Identifying genetic determinants of inflammatory pain in mice using a large-scale gene-targeted screen

Author

Wotton, Janine M, Peterson, Emma, Flenniken, Ann M, Bains, Rasneer S, Veeraragavan, Surabi, Bower, Lynette R, Bubier, Jason A, Parisien, Marc, Bezginov, Alexandr, Haselimashhadi, Hamed, Mason, Jeremy, Moore, Michayla A, Stewart, Michelle E, Clary, Dave A, Delbarre, Daniel J, Anderson, Laura C, D'Souza, Abigail, Goodwin, Leslie O, Harrison, Mark E, Huang, Ziyue, Mckay, Matthew, Qu, Dawei, Santos, Luis, Srinivasan, Subhiksha, Urban, Rachel, Vukobradovic, Igor, Ward, Christopher S, Willett, Amelia M, Braun, Robert E, Brown, Steve DM, Dickinson, Mary E, Heaney, Jason D, Kumar, Vivek, Lloyd, KC Kent, Mallon, Ann-Marie, McKerlie, Colin, Murray, Stephen A, Nutter, Lauryl MJ, Parkinson, Helen, Seavitt, John R, Wells, Sara, Samaco, Rodney C, Chesler, Elissa J, Smedley, Damian, Diatchenko, Luda, Baumbauer, Kyle M, Young, Erin E, Bonin, Robert P, Mandillo, Silvia, White, Jacqueline K, and International Mouse Phenotyping Consortium

Subjects
Nociception, Knockout, Autism, Freund's Adjuvant, Pain, Comorbidity, Basic Behavioral and Social Science, Medical and Health Sciences, Sensitization, Mice, Hargreaves, IMPC, Anesthesiology, Behavioral and Social Science, Genetics, Animals, 2.1 Biological and endogenous factors, Aetiology, Single-gene knockout mouse, Pain Measurement, Pain Research, Psychology and Cognitive Sciences, Neurosciences, Formalin, Screen, Complete Freund's adjuvant, Nocifensive behavior, International Mouse Phenotyping Consortium, Chronic Pain, von Frey, Biotechnology
Abstract

Identifying the genetic determinants of pain is a scientific imperative given the magnitude of the global health burden that pain causes. Here, we report a genetic screen for nociception, performed under the auspices of the International Mouse Phenotyping Consortium. A biased set of 110 single-gene knockout mouse strains was screened for 1 or more nociception and hypersensitivity assays, including chemical nociception (formalin) and mechanical and thermal nociception (von Frey filaments and Hargreaves tests, respectively), with or without an inflammatory agent (complete Freund's adjuvant). We identified 13 single-gene knockout strains with altered nocifensive behavior in 1 or more assays. All these novel mouse models are openly available to the scientific community to study gene function. Two of the 13 genes (Gria1 and Htr3a) have been previously reported with nociception-related phenotypes in genetically engineered mouse strains and represent useful benchmarking standards. One of the 13 genes (Cnrip1) is known from human studies to play a role in pain modulation and the knockout mouse reported herein can be used to explore this function further. The remaining 10 genes (Abhd13, Alg6, BC048562, Cgnl1, Cp, Mmp16, Oxa1l, Tecpr2, Trim14, and Trim2) reveal novel pathways involved in nociception and may provide new knowledge to better understand genetic mechanisms of inflammatory pain and to serve as models for therapeutic target validation and drug development.

Published
2022

4. Additional file 2 of Mendelian gene identification through mouse embryo viability screening

Author

Cacheiro, Pilar, Westerberg, Carl Henrik, Mager, Jesse, Dickinson, Mary E., Nutter, Lauryl M. J., Muñoz-Fuentes, Violeta, Hsu, Chih-Wei, Van den Veyver, Ignatia B., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Teboul, Lydia, Heaney, Jason D., Lloyd, K. C. Kent, Lanoue, Louise, Braun, Robert E., White, Jacqueline K., Creighton, Amie K., Laurin, Valerie, Guo, Ruolin, Qu, Dawei, Wells, Sara, Cleak, James, Bunton-Stasyshyn, Rosie, Stewart, Michelle, Harrisson, Jackie, Mason, Jeremy, Haseli Mashhadi, Hamed, Parkinson, Helen, Mallon, Ann-Marie, and Smedley, Damian

Abstract

Additional file 2: Fig. S1. WoL and cell essentiality scores. Fig. S2. WoL and cell essentiality categorisation. Fig. S3. WoL and additional gene features. Fig. S4. WoL and paralogues features. Fig. S5. WoL and additional disease features. Fig. S6. Prediction of early lethal genes. Fig. S7. Enrichment analysis of genes sharing attributes with a BIEM gene among the EL category.

Published
2022
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5. Additional file 1 of Mendelian gene identification through mouse embryo viability screening

Author

Cacheiro, Pilar, Westerberg, Carl Henrik, Mager, Jesse, Dickinson, Mary E., Nutter, Lauryl M. J., Muñoz-Fuentes, Violeta, Hsu, Chih-Wei, Van den Veyver, Ignatia B., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Teboul, Lydia, Heaney, Jason D., Lloyd, K. C. Kent, Lanoue, Louise, Braun, Robert E., White, Jacqueline K., Creighton, Amie K., Laurin, Valerie, Guo, Ruolin, Qu, Dawei, Wells, Sara, Cleak, James, Bunton-Stasyshyn, Rosie, Stewart, Michelle, Harrisson, Jackie, Mason, Jeremy, Haseli Mashhadi, Hamed, Parkinson, Helen, Mallon, Ann-Marie, and Smedley, Damian

Abstract

Additional file 1: Table S1. Gene features: Human cellular essential genes. Table S2. Gene features: Gene expression in human brain. Table S3. Gene features: Intolerance to variation metrics and paralogues. Table S4. Disease features. Table S5. HPO phenotypes Odds Ratios. Table S6. Comparison of our approach based on EL genes with other strategies based on standard scores thresholds: F-score. Table S7. Odds Ratios and 95% CI from multiple logistic regression analysis.

Published
2022
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6. Human and mouse essentiality screens as a resource for disease gene discovery

Author

Cacheiro, Pilar, Muñoz-Fuentes, Violeta, Westerberg, Henrik, Scott, R. H., Siddiq, A., Sieghart, A., Smith, K. R., Sosinsky, A., Spooner, W., Stevens, H. E., Stuckey, A., Sultana, R., Thomas, E. R. A., Konopka, Tomasz, Thompson, S. R., Tregidgo, C., Tucci, A., Walsh, E., Watters, S. A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Zarowiecki, M., Hsu, Chih-Wei, Marschall, Susan, Lengger, Christoph, Maier, Holger, Seisenberger, Claudia, Bürger, Antje, Kühn, Ralf, Schick, Joel, Hörlein, Andreas, Oritz, Oskar, Giesert, Florian, Christiansen, Audrey, Beig, Joachim, Kenyon, Janet, Codner, Gemma, Fray, Martin, Johnson, Sara J, Cleak, James, Szoke-Kovacs, Zsombor, Lafont, David, Vancollie, Valerie E, McLaren, Robbie S B, Lanza, Denise G, Hughes-Hallett, Lena, Rowley, Christine, Sanderson, Emma, Galli, Antonella, Tuck, Elizabeth, Green, Angela, Tudor, Catherine, Siragher, Emma, Dabrowska, Monika, Mazzeo, Cecilia Icoresi, Beaudet, Arthur L, Griffiths, Mark, Gannon, David, Doe, Brendan, Cockle, Nicola, Kirton, Andrea, Bottomley, Joanna, Ingle, Catherine, Ryder, Edward, Gleeson, Diane, Ramirez-Solis, Ramiro, Heaney, Jason D, Birling, Marie-Christine, Pavlovic, Guillaume, Ayadi, Abdel, Hamid, Meziane, About, Ghina Bou, Champy, Marie-France, Jacobs, Hugues, Wendling, Olivia, Leblanc, Sophie, Vasseur, Laurent, Fuchs, Helmut, Chesler, Elissa J, Kumar, Vivek, White, Jacqueline K, Svenson, Karen L, Wiegand, Jean-Paul, Anderson, Laura L, Wilcox, Troy, Clark, James, Ryan, Jennifer, Denegre, James, Gailus-Durner, Valerie, Stearns, Tim, Philip, Vivek, Witmeyer, Catherine, Bates, Lindsay, Seavey, Zachary, Stanley, Pamela, Willet, Amelia, Roper, Willson, Creed, Julie, Moore, Michayla, Sorg, Tania, Dorr, Alex, Fraungruber, Pamelia, Presby, Rose, Mckay, Matthew, Nguyen-Bresinsky, Dong, Goodwin, Leslie, Urban, Rachel, Kane, Coleen, Murray, Stephen A, Prochazka, Jan, Novosadova, Vendula, Lelliott, Christopher J, Wardle-Jones, Hannah, Wells, Sara, Teboul, Lydia, Cater, Heather, Stewart, Michelle, Hough, Tertius, Wurst, Wolfgang, Dickinson, Mary E, Sedlacek, Radislav, Adams, David J, Seavitt, John R, Tocchini-Valentini, Glauco, Mammano, Fabio, Braun, Robert E, McKerlie, Colin, Herault, Yann, de Angelis, Martin Hrabě, Mallon, Ann-Marie, Bucan, Maja, Lloyd, K C Kent, Brown, Steve D M, Parkinson, Helen, Meehan, Terrence F, Smedley, Damian, Consortium, Genomics England Research, Consortium, International Mouse Phenotyping, Ambrose, J. C., Arumugam, P., Baple, E. L., Nutter, Lauryl M J, Bleda, M., Boardman-Pretty, F., Boissiere, J. M., Boustred, C. R., Brittain, H., Caulfield, M. J., Chan, G. C., Craig, C. E. H., Daugherty, L. C., de Burca, A., Peterson, Kevin A, Devereau, A., Elgar, G., Foulger, R. E., Fowler, T., Furió-Tarí, P., Hackett, J. M., Halai, D., Hamblin, A., Henderson, S., Holman, J. E., Haselimashhadi, Hamed, Hubbard, T. J. P., Ibáñez, K., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S. E. A., Leong, I. U. S., Flenniken, Ann M, Lopez, F. J., Maleady-Crowe, F., Mason, J., McDonagh, E. M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., Odhams, C. A., Patch, C., Morgan, Hugh, Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Cacheiro, Pilar [0000-0002-6335-8208], Muñoz-Fuentes, Violeta [0000-0003-3574-546X], Nutter, Lauryl MJ [0000-0001-9619-146X], Peterson, Kevin A [0000-0001-8353-3694], Haselimashhadi, Hamed [0000-0001-7334-2421], Konopka, Tomasz [0000-0003-3042-4712], Hsu, Chih-Wei [0000-0002-9591-9567], Lanza, Denise G [0000-0001-8750-6933], Heaney, Jason D [0000-0001-8475-8828], Fuchs, Helmut [0000-0002-5143-2677], Gailus-Durner, Valerie [0000-0002-6076-0111], Lelliott, Christopher J [0000-0001-8087-4530], Adams, David J [0000-0001-9490-0306], Mammano, Fabio [0000-0003-3751-1691], McKerlie, Colin [0000-0002-2232-0967], Herault, Yann [0000-0001-7049-6900], de Angelis, Martin Hrabě [0000-0002-7898-2353], Lloyd, KC Kent [0000-0002-5318-4144], Smedley, Damian [0000-0002-5836-9850], Apollo - University of Cambridge Repository, Queen Mary University of London (QMUL), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, The Jackson Laboratory [Bar Harbor] (JAX), Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania, The Hospital for sick children [Toronto] (SickKids), Mount Sinai Hospital [Toronto, Canada] (MSH), MRC Harwell Institute [UK], Helmholtz Zentrum München = German Research Center for Environmental Health, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), The Wellcome Trust Sanger Institute [Cambridge], Technische Universität München = Technical University of Munich (TUM), Ludwig-Maximilians-Universität München (LMU), CNR - Italian National Research Council (CNR), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of California [Davis] (UC Davis), University of California (UC), J C Ambrose, P Arumugam, E L Baple, M Bleda, F Boardman-Pretty, J M Boissiere, C R Boustred, H Brittain, M J Caulfield, G C Chan, C E H Craig, L C Daugherty, A de Burca, A Devereau, G Elgar, R E Foulger, T Fowler, P Furió-Tarí, J M Hackett, D Halai, A Hamblin, S Henderson, J E Holman, T J P Hubbard, K Ibáñez, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, L Lahnstein, K Lawson, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, J Mason, E M McDonagh, L Moutsianas, M Mueller, N Murugaesu, A C Need, C A Odhams, C Patch, D Perez-Gil, D Polychronopoulos, J Pullinger, T Rahim, A Rendon, P Riesgo-Ferreiro, T Rogers, M Ryten, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, K R Smith, A Sosinsky, W Spooner, H E Stevens, A Stuckey, R Sultana, E R A Thomas, S R Thompson, C Tregidgo, A Tucci, E Walsh, S A Watters, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki, Susan Marschall, Christoph Lengger, Holger Maier, Claudia Seisenberger, Antje Bürger, Ralf Kühn, Joel Schick, Andreas Hörlein, Oskar Oritz, Florian Giesert, Joachim Beig, Janet Kenyon, Gemma Codner, Martin Fray, Sara J Johnson, James Cleak, Zsombor Szoke-Kovacs, David Lafont, Valerie E Vancollie, Robbie S B McLaren, Lena Hughes-Hallett, Christine Rowley, Emma Sanderson, Antonella Galli, Elizabeth Tuck, Angela Green, Catherine Tudor, Emma Siragher, Monika Dabrowska, Cecilia Icoresi Mazzeo, Mark Griffiths, David Gannon, Brendan Doe, Nicola Cockle, Andrea Kirton, Joanna Bottomley, Catherine Ingle, Edward Ryder, Diane Gleeson, Ramiro Ramirez-Solis, Marie-Christine Birling, Guillaume Pavlovic, Abdel Ayadi, Meziane Hamid, Ghina Bou About, Marie-France Champy, Hugues Jacobs, Olivia Wendling, Sophie Leblanc, Laurent Vasseur, Elissa J Chesler, Vivek Kumar, Jacqueline K White, Karen L Svenson, Jean-Paul Wiegand, Laura L Anderson, Troy Wilcox, James Clark, Jennifer Ryan, James Denegre, Tim Stearns, Vivek Philip, Catherine Witmeyer, Lindsay Bates, Zachary Seavey, Pamela Stanley, Amelia Willet, Willson Roper, Julie Creed, Michayla Moore, Alex Dorr, Pamelia Fraungruber, Rose Presby, Matthew Mckay, Dong Nguyen-Bresinsky, Leslie Goodwin, Rachel Urban, Coleen Kane, Herault, Yann, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
0301 basic medicine, Mutation rate, Cancer Research, [SDV]Life Sciences [q-bio], General Physics and Astronomy, methods [Genetic Association Studies], Disease, VARIANTS, Mice, Essential, 0302 clinical medicine, IMPC, Genetics research, Lethal allele, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Organism, ComputingMilieux_MISCELLANEOUS, Disease gene, Mice, Knockout, 0303 health sciences, Multidisciplinary, Genes, Essential, genetics [Disease], Genomics, R/BIOCONDUCTOR PACKAGE, DATABASE, UPDATE, GENOME, [SDV] Life Sciences [q-bio], Knockout mouse, Identification (biology), ddc:500, International Mouse Phenotyping Consortium, Technology Platforms, Biotechnology, Knockout, Science, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Genetics, medicine, Animals, Humans, Genetic variation, Clinical genetics, Gene, Genetic Association Studies, 030304 developmental biology, Disease model, Prevention, Human Genome, General Chemistry, medicine.disease, Developmental disorder, Good Health and Well Being, 030104 developmental biology, Genomics England Research Consortium, Genes, lcsh:Q, Generic health relevance, 030217 neurology & neurosurgery, Rare disease
Abstract

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery., Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Published
2020
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7. Additional file 1 of Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA disease

Author

Hiltunen, Anniina E., Kangas, Salla M., Ohlmeier, Steffen, Pietilä, Ilkka, Hiltunen, Jori, Tanila, Heikki, McKerlie, Colin, Subashika Govindan, Tuominen, Hannu, Kaarteenaho, Riitta, Hallman, Mikko, Uusimaa, Johanna, and Hinttala, Reetta

Abstract

Additional file 1: Detailed description of the materials and methods, supplementary figures S1- S11, and supplementary tables S1-S6. Materials and methods include generation of FINCA mouse, used animals, genotyping, Sanger equencing, histology, blood analysis, ISH, NPC culture, 2DE-DIGE, mass spectrometry, qPCR, immunoblotting, ICC, data analysis, and statistical considerations. Fig. S1 Genotyping and Sanger sequencing of three founders obtained from microinjections of Cas9 ribonucleoprotein and ssODN into mouse zygotes. Fig. S2 SDS-PAGE immunoblotting showing decrease of NHLRC2 in different brain regions and different tissues of Nhlrc2FINCA/− mice compared to wild type mice. Fig. S3 SDS-PAGE immunoblotting comparing the amount of NHLRC2 between wildtype, homozygous Nhlrc2FINCA/FINCA and compound heterozygous Nhlrc2FINCA/− mice. Fig. S4 Representative images of Nhlrc2+/+ and Nhlrc2FINCA/− mouse lung and liver sections. Fig. S5 NPC isolation and culture. Fig. S6 Representative 2D gel of NPCs (wild type). Fig. S7 STRING network analysis of identified proteins. Fig S8 SDS-PAGE immunoblot and 2D gel immunoblotof Nhlrc2+/+ and Nhlrc2FINCA/− NPC lysates with VCP antibodies. Fig. S9 hnRNP C2 ICC image of Nhlrc2+/+ and Nhlrc2FINCA/− NPCs showing normal cellular localization. Fig. S10 SDS-PAGE immunoblotting of Nhlrc2+/+ and Nhlrc2FINCA/− cerebellum and brainstem. Fig. S11 ISH of Nhlrc2FINCA/− mouse brain. Table S1 Genotyping primers. Table S2 qPCR primers. Table S3 Genotype distribution of Nhlrc2+/+ and Nhlrc2FINCA/− mouse offspring. Table S4 Blood values of Nhlrc2+/+ and Nhlrc2FINCA/− mice. Table S5 Detailed statistical and MS data about the proteins identified from 2DE-DIGE. Table S6. qPCR results of expression levels of genes identified in 2DE-DIGE.

Published
2020
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8. Genome-wide screening of mouse knockouts reveals novel genes required for normal integumentary and oculocutaneous structure and function

Author

Moore, Bret A., Flenniken, Ann M., Clary, Dave, Moshiri, Ata S., Nutter, Lauryl M. J., Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammad, McKerlie, Colin, Thomasy, Sara M., Lloyd, K. C. Kent, Murphy, Christopher J., Moshiri, Ala, Brown, Steve, Wells, Sara, Mallon, Ann-Marie, Beaudet, Arthur L., de Angelis, Martin Hrabe, Karp, Natasha, Braun, Bob, Herault, Yann, Gao, Xiang, Obata, Yuichi, Flicek, Paul, Meehan, Terrence, Parkinson, Helen, Smedley, Damian, Seong, J. K., Tocchini-Valentini, Glauco, and Mammano, Fabio

Subjects
DISORDER, Male, 0301 basic medicine, CATTLE, lcsh:Medicine, Disease, Genome, CHEDIAK-HIGASHI-SYNDROME, Mice, 0302 clinical medicine, Oculocutaneous, Genetics research, HERMANSKY-PUDLAK-SYNDROME, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, MUTATION, Mice, Knockout, Genetics, Multidisciplinary, Pigmentation, Integumentary system, RETINAL-PIGMENT EPITHELIUM, Phenotype, 3. Good health, Skin diseases, LIGHT, Albinism, Oculocutaneous, Albinism, Female, Integument, Integumentary System, International Mouse Phenotyping Consortium, Biotechnology, Knockout, Biology, Article, 03 medical and health sciences, medicine, Animals, Humans, Eye diseases, Gene, Gene knockout, Animal, GIANT GRANULES, MICE, MODEL, lcsh:R, Human Genome, medicine.disease, Disease Models, Animal, 030104 developmental biology, Disease Models, lcsh:Q, 030217 neurology & neurosurgery
Abstract

Oculocutaneous syndromes are often due to mutations in single genes. In some cases, mouse models for these diseases exist in spontaneously occurring mutations, or in mice resulting from forward mutatagenesis screens. Here we present novel genes that may be causative for oculocutaneous disease in humans, discovered as part of a genome-wide screen of knockout-mice in a targeted single-gene deletion project. The International Mouse Phenotyping Consortium (IMPC) database (data release 10.0) was interrogated for all mouse strains with integument abnormalities, which were then cross-referenced individually to identify knockouts with concomitant ocular abnormalities attributed to the same targeted gene deletion. The search yielded 307 knockout strains from unique genes with integument abnormalities, 226 of which have not been previously associated with oculocutaneous conditions. Of the 307 knockout strains with integument abnormalities, 52 were determined to have ocular changes attributed to the targeted deletion, 35 of which represent novel oculocutaneous genes. Some examples of various integument abnormalities are shown, as well as two examples of knockout strains with oculocutaneous phenotypes. Each of the novel genes provided here are potentially relevant to the pathophysiology of human integumentary, or oculocutaneous conditions, such as albinism, phakomatoses, or other multi-system syndromes. The novel genes reported here may implicate molecular pathways relevant to these human diseases and may contribute to the discovery of novel therapeutic targets.

Published
2019

9. Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author

Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, International Mouse Phenotyping Consortium, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Kent Lloyd, KC, Murphy, Christopher J, and Moshiri, Ala

Subjects
Genetics, International Mouse Phenotyping Consortium
Abstract

[This corrects the article DOI: 10.1038/s42003-018-0226-0.].

Published
2019

10. All in the Name: A Review of Current Standards and the Evolution of Histopathological Nomenclature for Laboratory Animals

Author

Schofield, PN, Elmore, Susan, Cardiff, Robert, Cesta, Mark, Gkoutos, Giorgios, Helton, Edward, Hoehndorf, Robert, Keenan, Charlotte, McKerlie, Colin, Sundberg, John, Schofield, Paul [0000-0002-5111-7263], and Apollo - University of Cambridge Repository

Abstract

The need for international collaboration in rodent pathology has evolved since the 1970s, and was initially driven by the new field of toxicologic pathology. First initiated by the World Health Organization’s International Agency for Research on Cancer for rodents, it has evolved to include pathology of the major species (rats, mice, guinea pigs, nonhuman primates, pigs, dogs, fish, rabbits) used in medical research, safety assessment and mouse pathology. The collaborative effort today is driven by the needs of the regulatory agencies in multiple countries, and by needs of research involving genetically engineered animals, for “basic” research, and for more translational preclinical models of human disease. These efforts led to the establishment of an international rodent pathology nomenclature program. Since that time, multiple collaborations for standardization of laboratory animal pathology nomenclature and diagnostic criteria have been developed, and just a few are described herein. Recently, approaches to a nomenclature that is amenable to sophisticated computation have been made available and implemented for large-scale programs in functional genomics and ageing. Most terminologies continue to evolve as the science of human and veterinary pathology continues to develop, but standardization and successful implementation remain as critical for scientific communication, now as ever in the history of veterinary nosology., Government of Canada through Genome Canada and Ontario Genomics (OGI-051), Commission of the European Community QLRI-1999-CT-0320, the Ellison Medical Foundation, and the National Institutes of Health (CA34196, CA089713, and AG038070-05)

Published
2018
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11. Corrigendum: High-throughput discovery of novel developmental phenotypes

Author

Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie Helmut Fuchs, Sarah M, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Nutter, Susan Newbigging Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, International Mouse Phenotyping Consortium, Wurst, Wolfgang, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, and Murray, Maja Bućan Stephen A

Subjects
General Science & Technology, International Mouse Phenotyping Consortium
Abstract

This corrects the article DOI: 10.1038/nature19356.

Published
2017

12. High-throughput discovery of novel developmental phenotypes

Author

Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie, Sarah M, Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Newbigging, Susan, Nutter, Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, International Mouse Phenotyping Consortium, Laboratory, Jackson, Infrastructure Nationale PHENOMIN, Institut Clinique De La Souris (ICS), Laboratories, Charles River, MRC Harwell, Toronto Centre For Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, De Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, Bućan, Maja, Murray, Stephen A, Bradley, Allan [0000-0002-2349-8839], and Apollo - University of Cambridge Repository

Subjects
General Science & Technology, Knockout, Sequence Homology, Penetrance, Inbred C57BL, Lethal, Polymorphism, Single Nucleotide, Imaging, Mice, Imaging, Three-Dimensional, Essential, Institut Clinique de la Souris, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, Disease, Wellcome Trust Sanger Institute, Aetiology, Polymorphism, Conserved Sequence, Mice, Knockout, Infrastructure Nationale PHENOMIN, Pediatric, Genes, Essential, MRC Harwell, Mammalian, Human Genome, Charles River Laboratories, Single Nucleotide, Embryo, Mammalian, RIKEN BioResource Center, High-Throughput Screening Assays, Mice, Inbred C57BL, Phenotype, Genes, Embryo, Toronto Centre for Phenogenomics, Three-Dimensional, Mutation, Congenital Structural Anomalies, Genes, Lethal, International Mouse Phenotyping Consortium, Jackson Laboratory, Genome-Wide Association Study, Biotechnology
Abstract

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

Published
2016

13. 685. Epithelium-Specific Gene Therapy Vector Protects Cftr Knockout Mice from Acute Lung Infection

Author

Keith Tanswell, Allan L. Coates, Forstner F. Janet, Jim Hu, Umadevi S. Sajjan, McKerlie Colin, and David R. Koehler

Subjects
Pharmacology, Lung, Genetic enhancement, respiratory system, Biology, medicine.disease, Cystic fibrosis, Molecular biology, Epithelium, respiratory tract diseases, Viral vector, medicine.anatomical_structure, Drug Discovery, Knockout mouse, Gene expression, Immunology, Genetics, medicine, Molecular Medicine, Respiratory epithelium, Molecular Biology
Abstract

Development of safe and effective vectors remains a major challenge for lung gene therapy. We developed a helper-dependent adenoviral vector for cystic fibrosis (CF) lung gene therapy, using epithelium-specific control elements to drive expression of the CF transmembrane conductance regulator (Cftr) gene. The vector expressed properly localized CFTR in human CF bronchial epithelial cells cultured at an air-liquid interface. Following a single intranasal dose, the vector expressed human CFTR specifically in the airway epithelium of mice, for up to 3 months. Acute inflammation was minimal to moderate. CFTR protein was also detected in the airway epithelium of 2 month-old mice that received one vector dose postnatally. Delivery of the vector to rabbit lung, in an aerosol containing surfactant, yielded strong gene expression (lacZ reporter) specifically in the airway epithelium, including trachea, bronchi, and bronchioles.

Published
2004

14. Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium

Author

Meehan, Terrence F, Conte, Nathalie, West, David B, Jacobsen, Julius O, Mason, Jeremy, Warren, Jonathan, Chen, Chao-Kung, Tudose, Ilinca, Relac, Mike, Matthews, Peter, Karp, Natasha, Santos, Luis, Fiegel, Tanja, Ring, Natalie, Westerberg, Henrik, Greenaway, Simon, Sneddon, Duncan, Morgan, Hugh, Codner, Gemma F, Stewart, Michelle E, Brown, James, Horner, Neil, International Mouse Phenotyping Consortium, Haendel, Melissa, Washington, Nicole, Mungall, Christopher J, Reynolds, Corey L, Gallegos, Juan, Gailus-Durner, Valerie, Sorg, Tania, Pavlovic, Guillaume, Bower, Lynette R, Moore, Mark, Morse, Iva, Gao, Xiang, Tocchini-Valentini, Glauco P, Obata, Yuichi, Cho, Soo Young, Seong, Je Kyung, Seavitt, John, Beaudet, Arthur L, Dickinson, Mary E, Herault, Yann, Wurst, Wolfgang, De Angelis, Martin Hrabe, Lloyd, KC Kent, Flenniken, Ann M, Nutter, Lauryl MJ, Newbigging, Susan, McKerlie, Colin, Justice, Monica J, Murray, Stephen A, Svenson, Karen L, Braun, Robert E, White, Jacqueline K, Bradley, Allan, Flicek, Paul, Wells, Sara, Skarnes, William C, Adams, David J, Parkinson, Helen, Mallon, Ann-Marie, Brown, Steve DM, and Smedley, Damian

Subjects
Male, Mice, Knockout, Disease Models, Animal, Gene Knockout Techniques, Mice, Phenotype, Genetic Diseases, Inborn, Animals, Humans, Female, Genetic Predisposition to Disease, 3. Good health
Abstract

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

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