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三种人类ARX突变在小鼠中导致了类似无脑回畸形以及伴有癫痫样多效性表型的智力迟钝。

Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice.

作者信息

Kitamura Kunio, Itou Yukiko, Yanazawa Masako, Ohsawa Maki, Suzuki-Migishima Rika, Umeki Yuko, Hohjoh Hirohiko, Yanagawa Yuchio, Shinba Toshikazu, Itoh Masayuki, Nakamura Kenji, Goto Yu-ichi

机构信息

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

出版信息

Hum Mol Genet. 2009 Oct 1;18(19):3708-24. doi: 10.1093/hmg/ddp318. Epub 2009 Jul 15.

Abstract

ARX (the aristaless-related homeobox gene) is a transcription factor that participates in the development of GABAergic and cholinergic neurons in the forebrain. Many ARX mutations have been identified in X-linked lissencephaly and mental retardation with epilepsy, and thus ARX is considered to be a causal gene for the two syndromes although the neurobiological functions of each mutation remain unclear. We attempted to elucidate the causal relationships between individual ARX mutations and disease phenotypes by generating a series of mutant mice. We generated three types of mice with knocked-in ARX mutations associated with X-linked lissencephaly (P353R) and mental retardation [P353L and 333ins(GCG)7]. Mice with the P355R mutation (equivalent to the human 353 position) that died after birth were significantly different in Arx transcript/protein amounts, GABAergic and cholinergic neuronal development, brain morphology and lifespan from mice with P355L and 330ins(GCG)7 but considerably similar to Arx-deficient mice with truncated ARX mutation in lissencephaly. Mice with the 330ins(GCG)7 mutation showed severe seizures and impaired learning performance, whereas mice with the P355L mutation exhibited mild seizures and only slightly impaired learning performance. Both types of mutant mice exhibited the mutation-specific lesser presence of GABAergic and cholinergic neurons in the striatum, medial septum and ventral forebrain nuclei when compared with wild-type mice. Present findings that reveal a causal relationship between ARX mutations and the pleiotropic phenotype in mice, suggest that the ARX-related syndrome, including lissencephaly or mental retardation, is caused by only the concerned ARX mutations without the involvement of other genetic factors.

摘要

ARX(无触须相关同源盒基因)是一种转录因子,参与前脑γ-氨基丁酸能(GABAergic)和胆碱能神经元的发育。在X连锁无脑回畸形伴癫痫的智力障碍中已鉴定出许多ARX突变,因此ARX被认为是这两种综合征的致病基因,尽管每个突变的神经生物学功能仍不清楚。我们试图通过培育一系列突变小鼠来阐明单个ARX突变与疾病表型之间的因果关系。我们培育了三种携带与X连锁无脑回畸形(P353R)和智力障碍相关的敲入ARX突变的小鼠[P353L和333ins(GCG)7]。出生后死亡的携带P355R突变(相当于人类353位)的小鼠在Arx转录本/蛋白量、GABA能和胆碱能神经元发育、脑形态和寿命方面与携带P355L和330ins(GCG)7的小鼠有显著差异,但与无脑回畸形中具有截短ARX突变的Arx缺陷小鼠相当相似。携带330ins(GCG)7突变的小鼠表现出严重癫痫发作和学习能力受损,而携带P355L突变的小鼠表现出轻度癫痫发作且学习能力仅略有受损。与野生型小鼠相比,这两种突变小鼠在纹状体、内侧隔区和腹侧前脑核中均表现出突变特异性的GABA能和胆碱能神经元数量减少。目前揭示ARX突变与小鼠多效性表型之间因果关系的研究结果表明,包括无脑回畸形或智力障碍在内的ARX相关综合征仅由相关的ARX突变引起,而无其他遗传因素的参与。

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