{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:56:14Z","timestamp":1787316974102,"version":"build-2736575974"},"reference-count":36,"publisher":"The Company of Biologists","issue":"5","license":[{"start":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T00:00:00Z","timestamp":1679356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["5-UM1-HG006370"],"award-info":[{"award-number":["5-UM1-HG006370"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013060","name":"European Molecular Biology Laboratory","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012116","name":"European Bioinformatics Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012116","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"crossref","award":["01KX1012"],"award-info":[{"award-number":["01KX1012"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Deutsches Zentrum f\u00fcr Diabetesforschung"},{"DOI":"10.13039\/501100013295","name":"Helmholtz Zentrum M\u00fcnchen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100013295","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Mouse models are relevant to studying the functionality of genes involved in human diseases; however, translation of phenotypes can be challenging. Here, we investigated genes related to monogenic forms of cardiovascular disease based on the Genomics England PanelApp and aligned them to International Mouse Phenotyping Consortium (IMPC) data. We found 153 genes associated with cardiomyopathy, cardiac arrhythmias or congenital heart disease in humans, of which 151 have one-to-one mouse orthologues. For 37.7% (57\/151), viability and heart data captured by electrocardiography, transthoracic echocardiography, morphology and pathology from embryos and young adult mice are available. In knockout mice, 75.4% (43\/57) of these genes showed non-viable phenotypes, whereas records of prenatal, neonatal or infant death in humans were found for 35.1% (20\/57). Multisystem phenotypes are common, with 58.8% (20\/34) of heterozygous (homozygous lethal) and 78.6% (11\/14) of homozygous (viable) mice showing cardiovascular, metabolic\/homeostasis, musculoskeletal, hematopoietic, nervous system and\/or growth abnormalities mimicking the clinical manifestations observed in patients. These IMPC data are critical beyond cardiac diagnostics given their multisystemic nature, allowing detection of abnormalities across physiological systems and providing a valuable resource to understand pleiotropic effects.<\/jats:p>","DOI":"10.1242\/dmm.049770","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T04:25:13Z","timestamp":1677212713000},"source":"Crossref","is-referenced-by-count":9,"title":["Knockout mice are an important tool for human monogenic heart disease studies"],"prefix":"10.1242","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6335-8208","authenticated-orcid":false,"given":"Pilar","family":"Cacheiro","sequence":"first","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London 1 , London EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2699-0068","authenticated-orcid":false,"given":"Nadine","family":"Spielmann","sequence":"additional","affiliation":[{"name":"Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich 2 , Munich 85764 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0514-1617","authenticated-orcid":false,"given":"Hamed Haseli","family":"Mashhadi","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory-European Bioinformatics Institute 3 , Hinxton CB10 1SD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5143-2677","authenticated-orcid":false,"given":"Helmut","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich 2 , Munich 85764 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6076-0111","authenticated-orcid":false,"given":"Valerie","family":"Gailus-Durner","sequence":"additional","affiliation":[{"name":"Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich 2 , Munich 85764 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5836-9850","authenticated-orcid":false,"given":"Damian","family":"Smedley","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London 1 , London EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7898-2353","authenticated-orcid":false,"given":"Martin Hrab\u0115","family":"de Angelis","sequence":"additional","affiliation":[{"name":"Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich 2 , Munich 85764 , Germany"},{"name":"Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universit\u00e4t M\u00fcnchen 4 , Freising 85354 , Germany"},{"name":"German Center for Diabetes Research (DZD) 5 , Neuherberg 85764 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"D1038","DOI":"10.1093\/nar\/gky1151","article-title":"OMIM.org: leveraging knowledge across phenotype\u2013gene relationships","volume":"47","author":"Amberger","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s13023-021-01839-9","article-title":"Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision","volume":"16","author":"Baldridge","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"934","DOI":"10.3389\/fendo.2019.00934","article-title":"High fidelity of mouse models mimicking human genetic skeletal disorders","volume":"10","author":"Brommage","year":"2019","journal-title":"Front. Endocrinol."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1007\/s00335-019-09813-4","article-title":"The dark genome and pleiotropy: challenges for precision medicine","volume":"30","author":"Brown","year":"2019","journal-title":"Mamm. Genome"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1007\/s00335-012-9427-x","article-title":"The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping","volume":"23","author":"Brown","year":"2012","journal-title":"Mamm. Genome"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s00335-019-09804-5","article-title":"New models for human disease from the International Mouse Phenotyping Consortium","volume":"30","author":"Cacheiro","year":"2019","journal-title":"Mamm. Genome"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/s41467-020-14284-2","article-title":"Human and mouse essentiality screens as a resource for disease gene discovery","volume":"11","author":"Cacheiro","year":"2020","journal-title":"Nat. Commun."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/s41586-019-1338-5","article-title":"Gene expression across mammalian organ development","volume":"571","author":"Cardoso-Moreira","year":"2019","journal-title":"Nature"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1038\/ng.3360","article-title":"Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics","volume":"47","author":"De Angelis","year":"2015","journal-title":"Nat. Genet."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/nature19356","article-title":"High-throughput discovery of novel developmental phenotypes","volume":"537","author":"Dickinson","year":"2016","journal-title":"Nature"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1186\/s13059-016-1024-y","article-title":"Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation and homozygous truncating mutations","volume":"17","author":"Doran","year":"2016","journal-title":"Genome Biol."},{"key":"2023032108253282200_","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4899-4541-9","volume-title":"An Introduction to the Bootstrap","author":"Efron","year":"1993"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1093\/ilar.43.2.66","article-title":"The mousetrap: what we can learn when the mouse model does not mimic the human disease","volume":"43","author":"Elsea","year":"2002","journal-title":"ILAR J."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1038\/s41431-021-00948-0","article-title":"TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility","volume":"29","author":"Engwerda","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"3635","DOI":"10.1038\/s41467-020-17374-3","article-title":"Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions","volume":"11","author":"Fahed","year":"2020","journal-title":"Nat. Commun."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"D1038","DOI":"10.1093\/nar\/gkac972","article-title":"The International Mouse Phenotyping Consortium: comprehensive knockout phenotyping underpinning the study of human disease","volume":"51","author":"Groza","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1093\/bioinformatics\/btz744","article-title":"Soft windowing application to improve analysis of high-throughput phenotyping data","volume":"36","author":"Haselimashhadi","year":"2020","journal-title":"Bioinformatics"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"e0242933","DOI":"10.1371\/journal.pone.0242933","article-title":"OpenStats: A robust and scalable software package for reproducible analysis of high-throughput phenotypic data","volume":"15","author":"Haselimashhadi","year":"2021","journal-title":"PLoS ONE"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1126\/science.aac9396","article-title":"De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies","volume":"350","author":"Homsy","year":"2015","journal-title":"Science"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1242\/dmm.024547","article-title":"Using the mouse to model human disease: increasing validity and reproducibility","volume":"9","author":"Justice","year":"2016","journal-title":"Dis. Model. Mech."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"e1002151","DOI":"10.1371\/journal.pbio.1002151","article-title":"Applying the ARRIVE guidelines to an in vivo database","volume":"13","author":"Karp","year":"2015","journal-title":"PLoS Biol."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"D1207","DOI":"10.1093\/nar\/gkaa1043","article-title":"The human phenotype ontology in 2021","volume":"49","author":"K\u00f6hler","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"D835","DOI":"10.1093\/nar\/gkz972","article-title":"ClinVar: improvements to accessing data","volume":"48","author":"Landrum","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/522151a","article-title":"Reproducibility: use mouse biobanks or lose them","volume":"522","author":"Lloyd","year":"2015","journal-title":"Nature"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1111\/ped.13272","article-title":"Cardiac manifestations of inherited metabolic disease in children","volume":"59","author":"Lloyd","year":"2017","journal-title":"Pediatr. Int."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1038\/s41588-019-0528-2","article-title":"PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels","volume":"51","author":"Martin","year":"2019","journal-title":"Nat. Genet."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1002\/ajmg.c.31570","article-title":"Genetic rodent models of brain disorders: Perspectives on experimental approaches and therapeutic strategies","volume":"175","author":"McGraw","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1161\/CIRCRESAHA.116.309396","article-title":"Dilated Cardiomyopathy","volume":"121","author":"McNally","year":"2017","journal-title":"Circ. Res."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"583932","DOI":"10.3389\/fgene.2020.583932","article-title":"The value of mouse models of rare diseases: a Spanish experience","volume":"11","author":"Murillo-Cuesta","year":"2020","journal-title":"Front. Genet."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1186\/s12967-018-1678-1","article-title":"Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail","volume":"16","author":"Pound","year":"2018","journal-title":"J. Transl. Med."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"e1004268","DOI":"10.1371\/journal.pgen.1004268","article-title":"Phenotype ontologies and cross-species analysis for translational research","volume":"10","author":"Robinson","year":"2014","journal-title":"PLoS Genet."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"R82","DOI":"10.1186\/gb-2013-14-7-r82","article-title":"A comparative phenotypic and genomic analysis of C57BL\/6J and C57BL\/6N mouse strains","volume":"14","author":"Simon","year":"2013","journal-title":"Genome Biol."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"bat025","DOI":"10.1093\/database\/bat025","article-title":"PhenoDigm: analyzing curated annotations to associate animal models with human diseases","volume":"2013","author":"Smedley","year":"2013","journal-title":"Database"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/s44161-022-00018-8","article-title":"Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy","volume":"1","author":"Spielmann","year":"2022","journal-title":"Nat. Cardiovasc. Res."},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1152\/physiolgenomics.00033.2003","article-title":"Developmental anatomy of the heart: a tale of mice and man","volume":"15","author":"Wessels","year":"2003","journal-title":"Physiol. Genomics"},{"key":"2023032108253282200_","doi-asserted-by":"publisher","first-page":"3158","DOI":"10.3390\/cells10113158","article-title":"Modeling rare human disorders in mice: the Finnish disease heritage","volume":"10","author":"Zarybnicky","year":"2021","journal-title":"Cells"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049770\/2506138\/dmm049770.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049770\/2647638\/dmm049770.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049770\/2647638\/dmm049770.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,26]],"date-time":"2023-03-26T07:22:39Z","timestamp":1679815359000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/16\/5\/dmm049770\/297258\/Knockout-mice-are-an-important-tool-for-human"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,21]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,5,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.049770","relation":{},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"value":"1754-8403","type":"print"},{"value":"1754-8411","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,21]]},"article-number":"dmm049770"}}