Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns
Two large-scale mouse gene knockout phenotyping campaigns have provided extensive data on the functions of thousands of mammalian genes. The ongoing International Mouse Phenotyping Consortium (IMPC), with the goal of examining all ∼20,000 mouse genes, has examined 5115 genes since 2011, and phenotyp...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2019-05-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/12/5/dmm038224 |
| _version_ | 1811207413419737088 |
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| author | Robert Brommage David R. Powell Peter Vogel |
| author_facet | Robert Brommage David R. Powell Peter Vogel |
| author_sort | Robert Brommage |
| collection | DOAJ |
| description | Two large-scale mouse gene knockout phenotyping campaigns have provided extensive data on the functions of thousands of mammalian genes. The ongoing International Mouse Phenotyping Consortium (IMPC), with the goal of examining all ∼20,000 mouse genes, has examined 5115 genes since 2011, and phenotypic data from several analyses are available on the IMPC website (www.mousephenotype.org). Mutant mice having at least one human genetic disease-associated phenotype are available for 185 IMPC genes. Lexicon Pharmaceuticals' Genome5000™ campaign performed similar analyses between 2000 and the end of 2008 focusing on the druggable genome, including enzymes, receptors, transporters, channels and secreted proteins. Mutants (4654 genes, with 3762 viable adult homozygous lines) with therapeutically interesting phenotypes were studied extensively. Importantly, phenotypes for 29 Lexicon mouse gene knockouts were published prior to observations of similar phenotypes resulting from homologous mutations in human genetic disorders. Knockout mouse phenotypes for an additional 30 genes mimicked previously published human genetic disorders. Several of these models have helped develop effective treatments for human diseases. For example, studying Tph1 knockout mice (lacking peripheral serotonin) aided the development of telotristat ethyl, an approved treatment for carcinoid syndrome. Sglt1 (also known as Slc5a1) and Sglt2 (also known as Slc5a2) knockout mice were employed to develop sotagliflozin, a dual SGLT1/SGLT2 inhibitor having success in clinical trials for diabetes. Clinical trials evaluating inhibitors of AAK1 (neuropathic pain) and SGLT1 (diabetes) are underway. The research community can take advantage of these unbiased analyses of gene function in mice, including the minimally studied ‘ignorome’ genes. |
| first_indexed | 2024-04-12T04:03:56Z |
| format | Article |
| id | doaj.art-4a4cb7ddfe3240e9bf397d4df0cc0ad3 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-12T04:03:56Z |
| publishDate | 2019-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-4a4cb7ddfe3240e9bf397d4df0cc0ad32022-12-22T03:48:39ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-05-0112510.1242/dmm.038224038224Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaignsRobert Brommage0David R. Powell1Peter Vogel2 Department of Metabolism Research, Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, TX 77381, USA Department of Metabolism Research, Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, TX 77381, USA St. Jude Children's Research Hospital, Pathology, MS 250, Room C5036A, 262 Danny Thomas Place, Memphis, TN 38105, USA Two large-scale mouse gene knockout phenotyping campaigns have provided extensive data on the functions of thousands of mammalian genes. The ongoing International Mouse Phenotyping Consortium (IMPC), with the goal of examining all ∼20,000 mouse genes, has examined 5115 genes since 2011, and phenotypic data from several analyses are available on the IMPC website (www.mousephenotype.org). Mutant mice having at least one human genetic disease-associated phenotype are available for 185 IMPC genes. Lexicon Pharmaceuticals' Genome5000™ campaign performed similar analyses between 2000 and the end of 2008 focusing on the druggable genome, including enzymes, receptors, transporters, channels and secreted proteins. Mutants (4654 genes, with 3762 viable adult homozygous lines) with therapeutically interesting phenotypes were studied extensively. Importantly, phenotypes for 29 Lexicon mouse gene knockouts were published prior to observations of similar phenotypes resulting from homologous mutations in human genetic disorders. Knockout mouse phenotypes for an additional 30 genes mimicked previously published human genetic disorders. Several of these models have helped develop effective treatments for human diseases. For example, studying Tph1 knockout mice (lacking peripheral serotonin) aided the development of telotristat ethyl, an approved treatment for carcinoid syndrome. Sglt1 (also known as Slc5a1) and Sglt2 (also known as Slc5a2) knockout mice were employed to develop sotagliflozin, a dual SGLT1/SGLT2 inhibitor having success in clinical trials for diabetes. Clinical trials evaluating inhibitors of AAK1 (neuropathic pain) and SGLT1 (diabetes) are underway. The research community can take advantage of these unbiased analyses of gene function in mice, including the minimally studied ‘ignorome’ genes.http://dmm.biologists.org/content/12/5/dmm038224Knockout miceMouse modelsPhenotypingPhenomicsTranslational medicine |
| spellingShingle | Robert Brommage David R. Powell Peter Vogel Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns Disease Models & Mechanisms Knockout mice Mouse models Phenotyping Phenomics Translational medicine |
| title | Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns |
| title_full | Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns |
| title_fullStr | Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns |
| title_full_unstemmed | Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns |
| title_short | Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns |
| title_sort | predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns |
| topic | Knockout mice Mouse models Phenotyping Phenomics Translational medicine |
| url | http://dmm.biologists.org/content/12/5/dmm038224 |
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