Meisler M H, Sprunger L K, Plummer N W, Escayg A, Jones J M
Department of Human Genetics, University of Michigan, Ann Arbor 48109-0618, USA.
Ann Med. 1997 Dec;29(6):569-74. doi: 10.3109/07853899709007484.
Analysis of the molecular defects in mouse mutants can identify candidate genes for human neurological disorders. During the past 2 years, mutations in sodium channels, calcium channels and potassium channels have been identified by positional cloning of the spontaneous mouse mutants motor endplate disease, tottering, lethargic and weaver. The phenotypes of four allelic mutations identified in the sodium channel gene Scn8a range from ataxia and muscle weakness through severe dystonia and progressive paralysis, indicating that human mutations in this gene could be associated with a variety of clinical syndromes. Mutations of the calcium channel subunits beta 4 in the lethargic mouse and alpha 1A in the tottering mouse have specific effects on cerebellar function. Targeted mutation of ligand-gated ion channels has also been used to generate new models of neurological disease. We will review these recent achievements and their implications for human neurological disease. The mouse studies indicate that mutations in ion channel genes are likely to be responsible for a broad spectrum of clinical phenotypes in human neurological disorders.
对小鼠突变体分子缺陷的分析能够鉴定出人类神经疾病的候选基因。在过去两年里，通过对自发小鼠突变体运动终板病、蹒跚症、嗜睡症和韦弗氏症进行定位克隆，已确定了钠通道、钙通道和钾通道中的突变。在钠通道基因Scn8a中鉴定出的四个等位基因突变的表型范围从共济失调和肌肉无力到严重肌张力障碍和进行性麻痹，这表明该基因的人类突变可能与多种临床综合征相关。嗜睡小鼠中钙通道亚基β4和蹒跚小鼠中α1A的突变对小脑功能有特定影响。配体门控离子通道的靶向突变也已用于生成神经疾病的新模型。我们将回顾这些最新成果及其对人类神经疾病的影响。小鼠研究表明，离子通道基因的突变很可能是人类神经疾病广泛临床表型的病因。
