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.

中文翻译：

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从小鼠基因敲除表型运动中预测人类疾病突变并确定药物靶标。

两次大规模的小鼠基因敲除表型研究已经为数千种哺乳动物基因的功能提供了广泛的数据。正在进行中的国际小鼠表型研究协会（IMPC）的目标是检查约20,000个小鼠基因，自2011年以来已检查了5115个基因，并且IMPC网站（www.mousephenotype.org）上提供了几种分析的表型数据。具有至少一种与人类遗传疾病相关的表型的突变小鼠可用于185 IMPC基因。Lexicon Pharmaceuticals的Genome5000™活动在2000年至2008年底之间进行了类似的分析，重点是可药物化的基因组，包括酶，受体，转运蛋白，通道和分泌的蛋白质。广泛研究了具有治疗意义的表型的突变体（4654个基因，具有3762个可行的成年纯合子系）。重要的是，在观察到由人类遗传疾病中的同源突变产生的相似表型之前，先公布了29种Lexicon小鼠基因敲除的表型。其他30种基因的基因敲除小鼠表型模仿了以前发表的人类遗传疾病。这些模型中的几种已帮助开发出有效的人类疾病治疗方法。例如学习Tph1基因敲除小鼠（缺乏外周血清素）有助于泰洛司他乙基的发展，这是一种批准的类癌综合症治疗方法。使用Sglt1（也称为Slc5a1）和Sglt2（也称为Slc5a2）敲除小鼠来开发sotagliflozin，这是一种在糖尿病临床试验中成功的双SGLT1 / SGLT2抑制剂。评估AAK1（神经性疼痛）和SGLT1（糖尿病）抑制剂的临床试验正在进行中。研究团体可以利用对小鼠基因功能的这些公正的分析，包括最少研究的“无知”基因。