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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.

Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns