MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
Hum Mol Genet. 2012 Oct 15;21(R1):R72-81. doi: 10.1093/hmg/dds318. Epub 2012 Aug 13.
Identifying genes involved in behavioural disorders in man is a challenge as the cause is often multigenic and the phenotype is modulated by environmental cues. Mouse mutants are a valuable tool for identifying novel pathways underlying specific neurological phenotypes and exploring the influence both genetic and non-genetic factors. Many human variants causing behavioural disorders are not gene deletions but changes in levels of expression or activity of a gene product; consequently, large-scale mouse ENU mutagenesis has the advantage over the study of null mutants in that it generates a range of point mutations that frequently mirror the subtlety and heterogeneity of human genetic lesions. ENU mutants have provided novel and clinically relevant functional information on genes that influence many aspects of mammalian behaviour, from neuropsychiatric endophenotypes to circadian rhythms. This review will highlight some of the most important findings that have been made using this method in several key areas of neurological disease research.
鉴定与人类行为障碍相关的基因是一项挑战，因为其病因通常是多基因的，表型受环境线索的调节。小鼠突变体是鉴定特定神经表型潜在新途径的有价值的工具，并可探索遗传和非遗传因素的影响。许多导致行为障碍的人类变异不是基因缺失，而是基因产物表达或活性水平的变化；因此，大规模的小鼠ENU 诱变相对于研究缺失突变体具有优势，因为它产生了一系列点突变，这些突变经常反映了人类遗传损伤的微妙性和异质性。ENU 突变体为影响哺乳动物行为许多方面的基因提供了新颖且具有临床相关性的功能信息，从神经精神内表型到昼夜节律。本文将重点介绍使用该方法在神经疾病研究的几个关键领域取得的一些最重要的发现。
