Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice
Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice
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DOI：
10.1093/hmg/ddp318
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发表时间：
2009-10-01
影响因子：
3.5
通讯作者：
Goto, Yu-ichi
中科院分区：
文献类型：
--
作者：
Kitamura, Kunio;Itou, Yukiko;Goto, Yu-ichi
ARX（aristaless-related homeobox gene）是一种转录因子，参与前脑GABA能和胆碱能神经元的发育。在X连锁无脑畸形和精神发育迟滞伴癫痫中发现了许多ARX突变，因此认为ARX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尚不清楚。我们试图通过产生一系列突变小鼠来阐明单个ARX突变和疾病表型之间的因果关系。我们产生了三种类型的敲入ARX突变的小鼠，这些突变与X连锁无脑畸形（P353 R）和精神发育迟滞[P353 L和333 ins（GCG）7]相关。出生后死亡的具有P355 R突变（相当于人类353位置）的小鼠在Arx转录物/蛋白量、GABA能和胆碱能神经元发育、脑形态和寿命方面与具有P355 L和330 ins（GCG）7的小鼠显著不同，但与无脑畸形中具有截短的Arx突变的Arx缺陷小鼠相当相似。具有330 ins（GCG）7突变的小鼠表现出严重的癫痫发作和学习能力受损，而具有P355 L突变的小鼠表现出轻度癫痫发作和仅轻微的学习能力受损。与野生型小鼠相比，两种类型的突变小鼠在纹状体、内侧隔和腹侧前脑核中均表现出GABA能和胆碱能神经元的突变特异性减少。目前的研究结果揭示了ARX突变和小鼠多效性表型之间的因果关系，表明ARX相关综合征，包括无脑畸形或智力低下，是由相关的ARX突变引起的，而不涉及其他遗传因素。
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.