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1. Impact of essential genes on the success of genome editing experiments generating 3313 new genetically engineered mouse lines

Author

Hillary Elrick, Kevin A. Peterson, Brandon J. Willis, Denise G. Lanza, Elif F. Acar, Edward J. Ryder, Lydia Teboul, Petr Kasparek, Marie-Christine Birling, David J. Adams, Allan Bradley, Robert E. Braun, Steve D. Brown, Adam Caulder, Gemma F. Codner, Francesco J. DeMayo, Mary E. Dickinson, Brendan Doe, Graham Duddy, Marina Gertsenstein, Leslie O. Goodwin, Yann Hérault, Lauri G. Lintott, K. C. Kent Lloyd, Isabel Lorenzo, Matthew Mackenzie, Ann-Marie Mallon, Colin McKerlie, Helen Parkinson, Ramiro Ramirez-Solis, John R. Seavitt, Radislav Sedlacek, William C. Skarnes, Damien Smedley, Sara Wells, Jacqueline K. White, Joshua A. Wood, International Mouse Phenotyping Consortium, Stephen A. Murray, Jason D. Heaney, and Lauryl M. J. Nutter

Subjects
Cas9, Genome editing, Mouse, Knockout, Medicine, Science
Abstract

Abstract The International Mouse Phenotyping Consortium (IMPC) systematically produces and phenotypes mouse lines with presumptive null mutations to provide insight into gene function. The IMPC now uses the programmable RNA-guided nuclease Cas9 for its increased capacity and flexibility to efficiently generate null alleles in the C57BL/6N strain. In addition to being a valuable novel and accessible research resource, the production of 3313 knockout mouse lines using comparable protocols provides a rich dataset to analyze experimental and biological variables affecting in vivo gene engineering with Cas9. Mouse line production has two critical steps – generation of founders with the desired allele and germline transmission (GLT) of that allele from founders to offspring. A systematic evaluation of the variables impacting success rates identified gene essentiality as the primary factor influencing successful production of null alleles. Collectively, our findings provide best practice recommendations for using Cas9 to generate alleles in mouse essential genes, many of which are orthologs of genes linked to human disease.

Published
2024
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2. Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance

Author

Bridget M. Stroup, Xiaohui Li, Sara Ho, Haonan Zhouyao, Yuqing Chen, Safa Ani, Brian Dawson, Zixue Jin, Ronit Marom, Ming-Ming Jiang, Isabel Lorenzo, Daniel Rosen, Denise Lanza, Nathalie Aceves, Sara Koh, John R. Seavitt, Jason D. Heaney, Brendan Lee, and Lindsay C. Burrage

Subjects
osteoporosis, osteoblast, igf-1, lysinuric protein intolerance, slc7a7, arginine, Medicine, Pathology, RB1-214
Published
2023
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3. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

Paul Flicek, Raffaele Teperino, Lydia Teboul, Thomas Werner, Marie-France Champy, Christopher J. Lelliott, Graham R. Williams, Jacqueline K. White, Gregor Miller, Mary E. Dickinson, Ann M Flenniken, Radislav Sedlacek, Martin Hrabé de Angelis, John R. Seavitt, Peter I. Croucher, Maria del Mar Muniz Moreno, Sara Wells, Jan Rozman, Terrence F. Meehan, Kristian F Odfalk, Juan Gallegos, J. H. Duncan Bassett, Mohammed Selloum, John G. Logan, Sylvie Jacquot, Elena J. Ghirardello, Robert Braun, Frantisek Spoutil, Kevin C K Lloyd, Lore Becker, Stephen A. Murray, Jan Prochazka, Elif F. Acar, Taylor S Vales, Michelle Simon, Helmut Fuchs, Nadine Spielmann, Mark Griffiths, Piia Keskivali-Bond, Valerie Gailus-Durner, Tania Sorg, Christine Schütt, Jeremy Mason, Helen Parkinson, Karen L. Svenson, Abdel Ayadi, Anna L Swan, Jason D. Heaney, Colin McKerlie, Wolfgang Wurst, Ann-Marie Mallon, Heather Cater, Stefanie Leuchtenberger, Harald Grallert, Steve D.M. Brown, Stefan Brandmaier, Yann Herault, Philipp Mayer-Kuckuk, Corey L. Reynolds, Ala Moshiri, Robert Brommage, Derek D. Cissell, Lauryl M J Nutter, Connor Lally, MRC Harwell Institute [UK], German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), 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), Helmholtz-Zentrum München (HZM), The Wellcome Trust Sanger Institute [Cambridge], University of Michigan [Ann Arbor], University of Michigan System, University of California [Davis] (UC Davis), University of California, Baylor College of Medicine (BCM), Baylor University, European Molecular Biology Laboratory [Hinxton], University of Toronto, University of Manitoba [Winnipeg], Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], French National Infrastructure for Mouse Phenogenomics (PHENOMIN), The Jackson Laboratory [Bar Harbor] (JAX), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Imperial College London, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Garvan Institute of Medical Research [Sydney, Australia], St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Université de Nouvelle-Galles du Sud - UNSW [Sydney, Australia], Mundlos, Stefan, Wellcome Trust, Commission of the European Communities, European Commission, Herault, Yann, Helmholtz Zentrum München = German Research Center for Environmental Health, University of California (UC), Garvan Institute of medical research, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Technische Universität München [München] (TUM), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Swan, Anna L [0000-0003-1810-3756], Rozman, Jan [0000-0002-8035-8904], Del Mar Muñiz Moreno, Maria [0000-0002-2662-890X], Leuchtenberger, Stefanie [0000-0003-2475-0810], Brommage, Robert [0000-0002-9947-3822], Grallert, Harald [0000-0002-6876-9655], Werner, Thomas [0000-0003-0402-4539], Teperino, Raffaele [0000-0001-8815-1409], Becker, Lore [0000-0002-6890-4984], Miller, Gregor [0000-0002-4281-4905], Seavitt, John R [0000-0003-3209-3187], Cissell, Derek D [0000-0002-6450-422X], Acar, Elif F [0000-0003-2908-7691], Lelliott, Christopher J [0000-0001-8087-4530], Braun, Robert E [0000-0003-3856-9465], Cater, Heather [0000-0002-8696-6070], Flicek, Paul [0000-0002-3897-7955], Ghirardello, Elena J [0000-0002-1100-9217], Heaney, Jason D [0000-0001-8475-8828], Lally, Connor [0000-0002-3801-1966], Logan, John G [0000-0003-2801-700X], Mason, Jeremy [0000-0002-2796-5123], Nutter, Lauryl MJ [0000-0001-9619-146X], Odfalk, Kristian F [0000-0003-4152-4583], Prochazka, Jan [0000-0003-4675-8995], Selloum, Mohammed [0000-0003-4057-3519], Spoutil, Frantisek [0000-0002-7310-3487], Svenson, Karen L [0000-0002-7928-1911], Vales, Taylor S [0000-0001-9751-5681], Wells, Sara E [0000-0002-0572-0600], White, Jacqueline K [0000-0001-6268-2826], Sedlacek, Radislav [0000-0002-3352-392X], Wurst, Wolfgang [0000-0003-4422-7410], Lloyd, KC Kent [0000-0002-5318-4144], Williams, Graham R [0000-0002-8555-8219], Herault, Yann [0000-0001-7049-6900], Brown, Steve DM [0000-0002-0617-4824], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository

Subjects
Male, Osteoporosis, genetics [Gene Expression Regulation], Transgenic, Transcriptome, Mice, 0302 clinical medicine, Animal Cells, Aetiology, Musculoskeletal System, Connective Tissue Cells, Genetics & Heredity, 0303 health sciences, Genomics, 3. Good health, Cellular Types, musculoskeletal diseases, Genotype, In silico, 1.1 Normal biological development and functioning, 03 medical and health sciences, genetics [Osteoporosis], Rheumatology, pathology [Osteoblasts], Genetic, Genome-Wide Association Studies, Genetics, GENOME-WIDE ASSOCIATION, Molecular Biology, Skeleton, Ecology, Evolution, Behavior and Systematics, METAANALYSIS, metabolism [Osteoblasts], 0604 Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Osteoblasts, IDENTIFICATION, Biology and Life Sciences, Computational Biology, medicine.disease, COLLAGEN, Biological Tissue, OSTEOGENESIS IMPERFECTA, DISCOVERY, IMPC Consortium, Mutation, Animal Studies, Developmental Biology, Candidate gene, Cancer Research, Bone density, Gene Expression, Osteoclasts, [SDV.GEN] Life Sciences [q-bio]/Genetics, QH426-470, Bone remodeling, Bone Density, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Protein Interaction Maps, Connective Tissue Diseases, Promoter Regions, Genetic, Genetics (clinical), Bone mineral, Sex Characteristics, genetics [Bone Density], metabolism [Osteoclasts], Genetic Pleiotropy, Animal Models, pathology [Osteoclasts], Phenotype, DIFFERENTIATION, Experimental Organism Systems, ANIMAL-MODELS, Connective Tissue, SEX, Female, Anatomy, Technology Platforms, Life Sciences & Biomedicine, Research Article, metabolism [Osteoporosis], Mouse Models, 030209 endocrinology & metabolism, Mice, Transgenic, Biology, Research and Analysis Methods, Promoter Regions, Model Organisms, Underpinning research, medicine, Animals, ddc:610, Bone, 030304 developmental biology, Human Genetics, Cell Biology, Genome Analysis, Gene Ontology, Gene Expression Regulation, Musculoskeletal, Genome-Wide Association Study
Abstract

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease., Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.

Published
2021
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4. A global Slc7a7 knockout mouse model demonstrates characteristic phenotypes of human lysinuric protein intolerance

Author

John R. Seavitt, J. P. Barrish, Luan D. Truong, Lindsay C. Burrage, Farrah Kheradmand, Cheng Yen Chang, Denise G. Lanza, Yuqing Chen, Brian Dawson, Qin Sun, Jason D. Heaney, Xiaohui Li, Brendan Lee, Audrey E. Christiansen, Chih-Wei Hsu, Jennie R. Green, Ronit Marom, Safa Ani, Mary E. Dickinson, Ingo Grafe, Bridget M. Stroup, and Ming Ming Jiang

Subjects
medicine.medical_specialty, Arginine, Renal cortex, Biology, Kidney, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal medicine, Genetics, medicine, Animals, Humans, Amino Acids, Molecular Biology, Amino Acid Metabolism, Inborn Errors, Genetics (clinical), 030304 developmental biology, Mice, Knockout, 0303 health sciences, Amino Acid Transport System y+L, General Medicine, Exons, X-Ray Microtomography, Ornithine, medicine.disease, Phenotype, Lysinuric protein intolerance, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, chemistry, Aminoaciduria, Knockout mouse, General Article, Pulmonary alveolar proteinosis, 030217 neurology & neurosurgery
Abstract

Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.

Published
2020

5. The occurrence of tarsal injuries in male mice of C57BL/6N substrains in multiple international mouse facilities

Author

Bonnie L. Lyons, Juan Antonio Aguilar-Pimentel, Colin McKerlie, Sara Wells, Michelle Stewart, Eleanor Herbert, John R. Seavitt, Rosalinda A Doty, Jean-Paul Wiegand, Liane Hobson, Ann M Flenniken, Lauryl M. J. Nutter, Brenda Kick, Dawei Qu, Jacqueline K. White, Martin Hrabe de Angelis, Marie Hutchison, Mary E Dickinson, and Cheryl L. Scudamore

Subjects
Male, 0301 basic medicine, Internationality, Adult male, Physiology, Inbred Strains, Social Sciences, Male mice, Hindlimb, Diagnostic Radiology, Tendons, Mice, 0302 clinical medicine, Skeletal Joints, Medicine and Health Sciences, Psychology, Medicine, Animal Husbandry, Musculoskeletal System, Animal Management, Histological examination, Mammals, 0303 health sciences, Multidisciplinary, Animal Behavior, Radiology and Imaging, Eukaryota, Agriculture, Anatomy, Bone Imaging, 3. Good health, Experimental Organism Systems, Connective Tissue, Lameness, Vertebrates, Gait Analysis, Research Article, animal structures, Imaging Techniques, Science, C57bl 6n, Research and Analysis Methods, Animal Welfare, Rodents, 03 medical and health sciences, Diagnostic Medicine, Animals, 030304 developmental biology, Behavior, Biological Locomotion, business.industry, Organisms, Biology and Life Sciences, Tarsal Bones, X-Ray Radiography, Mice, Inbred C57BL, body regions, Biological Tissue, 030104 developmental biology, Amniotes, Animal Studies, Calcaneus, Tomography, X-Ray Computed, business, Zoology, 030217 neurology & neurosurgery, Sudden onset
Abstract

Dislocation in hindlimb tarsals are being observed at a low, but persistent frequency in adult male mice from C57BL/6N substrains. Clinical signs included a sudden onset of mild to severe unilateral or bilateral tarsal abduction, swelling, abnormal hindlimb morphology and lameness. Contraction of digits and gait abnormalities were noted in multiple cases. Radiographical and histological examination revealed caudal dislocation of the calcaneus and partial dislocation of the calcaneoquartal (calcaneous-tarsal bone IV) joint. The detection, frequency, and cause of this pathology in five large mouse production and phenotyping centres (MRC Harwell, UK; The Jackson Laboratory, USA; The Centre for Phenogenomics, Canada; German Mouse Clinic, Germany; Baylor College of Medicine, USA) are discussed.

Published
2020

6. Rapid and Integrative Discovery of Retina Regulatory Molecules

Author

Melanie A. Samuel, Danye Jiang, Courtney A. Burger, Julia Wang, Jonathan Alevy, Fenge Li, Seon Young Kim, Peter D. Westenskow, Brian I. Liu, Ritu Bohat, Angelina Gaspero, Shinya Yamamoto, Uchechukwu Udensi, Chih-Wei Hsu, John R. Seavitt, Nicholas E. Albrecht, Sowmya Kalaga, Arthur L. Beaudet, Mary E. Dickinson, Monica J. Justice, and Chinwe Asomugha

Subjects
Neurons, 0301 basic medicine, Nervous system, Retina, Retinal, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Regulatory molecules, Synapse, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, medicine.anatomical_structure, chemistry, Synapses, medicine, Humans, Neuron, Gene, Neuroscience, Regulator gene
Abstract

Retinal function relies on precisely organized neurons and synapses and a properly patterned vasculature to support them. Alterations in these features can result in vision loss. However, our understanding of retinal organization pathways remains incomplete because of a lack of methods to rapidly identify neuron and vasculature regulators in mammals. Here we developed a pipeline for the identification of neural and synaptic integrity genes by high-throughput retinal screening (INSiGHT) that analyzes candidate expression, vascular patterning, cellular organization, and synaptic arrangement. Using this system, we examined 102 mutant mouse lines and identified 16 unique retinal regulatory genes. Fifteen of these candidates are identified as novel retina regulators, and many (9 of 16) are associated with human neural diseases. These results expand the genetic landscape involved in retinal circuit organization and provide a road map for continued discovery of mammalian retinal regulators and disease-causing alleles.

Published
2018
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7. CRIPTexonic deletion and a novel missense mutation in a female with short stature, dysmorphic features, microcephaly, and pigmentary abnormalities

Author

Christine M. Eng, Theodore Chiang, Weimin Bi, John R. Seavitt, Audrey Chan, Stephen A. Murray, Magalie S. Leduc, Wenmiao Zhu, Haley Streff, Seema R. Lalani, Zhiyv Niu, Yaping Yang, and Irene Miloslavskaya

Subjects
0301 basic medicine, Proband, Microcephaly, DNA Mutational Analysis, Mutation, Missense, Dwarfism, Biology, Article, 03 medical and health sciences, Exon, 0302 clinical medicine, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Global developmental delay, Syndactyly, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, Sequence Deletion, Facies, Exons, medicine.disease, Pedigree, Phenotype, 030104 developmental biology, Amino Acid Substitution, Child, Preschool, Female, Primordial dwarfism, 030217 neurology & neurosurgery
Abstract

Mutations in CRIPT encoding cysteine-rich PDZ domain-binding protein are rare, and to date have been reported in only two patients with autosomal recessive primordial dwarfism and distinctive facies. Here, we describe a female with biallelic mutations in CRIPT presenting with postnatal growth retardation, global developmental delay, and dysmorphic features including frontal bossing, high forehead, and sparse hair and eyebrows. Additional clinical features included high myopia, admixed hyper- and hypopigmented macules primarily on the face, arms, and legs, and syndactyly of 4-5 toes bilaterally. Using whole exome sequencing (WES) and chromosomal microarray analysis (CMA), we detected a c.8G>A (p.C3Y) missense variant in exon 1 of the CRIPT gene inherited from the mother and a 1,331 bp deletion encompassing exon 1, inherited from the father. The c.8G>A (p.C3Y) missense variant in CRIPT was apparently homozygous in the proband due to the exon 1 deletion. Our findings illustrate the clinical utility of combining WES with copy number variant (CNV) analysis to provide a molecular diagnosis to patients with rare Mendelian disorders. Our findings also illustrate the clinical spectrum of CRIPT related mutations. © 2016 Wiley Periodicals, Inc.

Published
2016
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8. Biallelic variants in OTUD6B cause an intellectual disability syndrome associated with seizures and dysmorphic features

Author

Christine M. Eng, Thomas Besnard, Ingo Helbig, Holger Lerche, Bülent Kara, H. Hjalgrim, Peter-Michael Kloetzel, Mahmoud Y. Issa, Frédéric Ebstein, Isabelle Hazart, M. Cecilia Ljungberg, Eric LeGuern, Yaping Yang, Jill A. Rosenfeld, Rikke S. Møller, Alicia Braxton, Lindsay C. Burrage, Sarah Weckhuysen, Felix Rosenow, Peter De Jonghe, Johannes R. Lemke, Hiltrud Muhle, Elizabeth Roeder, Mary E. Dickinson, Nina Barišić, Bassam Abu-Libdeh, Federico Zara, Sara Wells, Carla Marini, Jennifer L. Silhavy, Marcus J. Miller, Maha S. Zaki, Bertrand Isidor, Teresa Santiago-Sim, LaDonna Immken, Andrea Lehmann, Joseph G. Gleeson, Karl Martin Klein, Mari Tokita, A Suls, Honey Nagakura, Rudi Balling, Rosa Guerrero-López, Katalin Sterbova, Benjamin Cogné, John R. Seavitt, Pasquale Striano, Maher Shahrour, Stéphanie Baulac, Renzo Guerrini, Sara Johnson, Lydia Teboul, Stéphane Bézieau, Kiely N. James, Katia Hardies, Orly Elpeleg, Dana Craiu, Jason D. Heaney, Sébastien Küry, Yvonne G. Weber, Zaid Afawi, Weimin Bi, Rebecca O. Littlejohn, Patrick May, Jose Serratosa, Magdalena Walkiewicz, Johanna A. Jähn, and EuroEPINOMICS RES Consortium Autos

Subjects
0301 basic medicine, Male, Microcephaly, Proteasome Endopeptidase Complex, Adolescent, Protein degradation, Deubiquitinating enzyme, 03 medical and health sciences, Mice, Ubiquitin, Seizures, Report, Intellectual Disability, Intellectual disability, Endopeptidases, Genetics, medicine, Journal Article, Animals, Humans, Abnormalities, Multiple, Global developmental delay, Child, Genetics (clinical), biology, Syndrome, medicine.disease, Hypotonia, Musculoskeletal Abnormalities, Pedigree, Disease Models, Animal, 030104 developmental biology, Proteasome, Child, Preschool, biology.protein, Female, Human medicine, medicine.symptom, Gene Deletion
Abstract

Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain(OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.

Published
2017
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9. High-throughput discovery of novel developmental phenotypes

Author

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

Subjects
0301 basic medicine, Mouse, Mammalian embryology, Sequence Homology, Genome-wide association study, Penetrance, Development, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Mice, Imaging, Three-Dimensional, medicine, Lethal allele, Animals, Humans, Disease, Gene, Gene knockout, Conserved Sequence, Genetics, Mice, Knockout, Mutation, Multidisciplinary, Genes, Essential, Embryo, Mammalian, Phenotype, High-Throughput Screening Assays, Mice, Inbred C57BL, 030104 developmental biology, Mutagenesis, Genes, Lethal, Genome-Wide Association Study
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
2015
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10. Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

Author

Lindsay C. Burrage, John J. Reynolds, Nissan Vida Baratang, Jennifer B. Phillips, Jeremy Wegner, Ashley McFarquhar, Martin R. Higgs, Audrey E. Christiansen, Denise G. Lanza, John R. Seavitt, Mahim Jain, Xiaohui Li, David A. Parry, Vandana Raman, David Chitayat, Ivan K. Chinn, Alison A. Bertuch, Lefkothea Karaviti, Alan E. Schlesinger, Dawn Earl, Michael Bamshad, Ravi Savarirayan, Harsha Doddapaneni, Donna Muzny, Shalini N. Jhangiani, Christine M. Eng, Richard A. Gibbs, Weimin Bi, Lisa Emrick, Jill A. Rosenfeld, John Postlethwait, Monte Westerfield, Mary E. Dickinson, Arthur L. Beaudet, Emmanuelle Ranza, Celine Huber, Valérie Cormier-Daire, Wei Shen, Rong Mao, Jason D. Heaney, Jordan S. Orange, Débora Bertola, Guilherme L. Yamamoto, Wagner A.R. Baratela, Merlin G. Butler, Asim Ali, Mehdi Adeli, Daniel H. Cohn, Deborah Krakow, Andrew P. Jackson, Melissa Lees, Amaka C. Offiah, Colleen M. Carlston, John C. Carey, Grant S. Stewart, Carlos A. Bacino, Philippe M. Campeau, Brendan Lee, David R. Adams, Aaron Aday, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Mahshid S. Azamian, Eva Baker, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Manish J. Butte, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jean M. Davidson, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Annika M. Dries, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Gregory M. Enns, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Frances High, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, 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, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Jason D. Merker, Thomas O. Metz, Matthew Might, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, James P. Orengo, 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, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, David A. Sweetser, Queenie K.-G. Tan, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Eric Vilain, Tiphanie P. Vogel, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jijun Wan, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Yaping Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Allison Zheng

Subjects
Adult, Pathology, medicine.medical_specialty, Adolescent, DNA repair, Osteochondrodysplasias, Short stature, Article, 03 medical and health sciences, Mice, Young Adult, 0302 clinical medicine, Chromosomal Instability, Exome Sequencing, Genetics, medicine, Homologous chromosome, Animals, Humans, Allele, Child, Zebrafish, Genetics (clinical), Exome sequencing, Alleles, Cells, Cultured, Genetic Association Studies, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Spondyloepimetaphyseal dysplasia, biology, NF-kappa B, Genetic Variation, Fibroblasts, medicine.disease, biology.organism_classification, 3. Good health, Musculoskeletal Abnormalities, Dysplasia, Child, Preschool, Female, medicine.symptom, 030217 neurology & neurosurgery, DNA Damage
Abstract

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

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