Behavioral and neuroanatomical analyses in a genetic mouse model of 2q13 duplication
Behavioral and neuroanatomical analyses in a genetic mouse model of 2q13 duplication
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DOI：
10.1111/gtc.12487
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发表时间：
2017-05
期刊：
影响因子：
2.1
通讯作者：
K. Kishimoto;J. Nomura;J. Ellegood;Keita Fukumoto;J. Lerch;D. Moreno-De-Luca;T. Bourgeron;Kota Tamada;T. Takumi
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文献类型：
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作者：
K. Kishimoto;J. Nomura;J. Ellegood;Keita Fukumoto;J. Lerch;D. Moreno-De-Luca;T. Bourgeron;Kota Tamada;T. Takumi
人类染色体2 q13的重复已经在包括自闭症谱系障碍在内的神经发育障碍患者中报道。肾单位缺损-1（NPHP 1）被确定为家族性青少年1型肾单位缺损和Joubert综合征（一种常染色体隐性遗传神经发育障碍，特征为小脑和脑干畸形、张力减退、发育迟缓、共济失调，有时伴有认知障碍）染色体2 q13上最小缺失的致病基因。NPHP 1编码一种纤毛蛋白，肾囊蛋白-1，它在大脑中表达，但它在大脑中的功能在很大程度上仍然未知。在这项研究中，我们产生了基于细菌人工染色体的转基因小鼠，称为2 q13 dup，它重现了人类染色体2 q13复制，并含有一个额外的Nphp 1转基因拷贝。为了分析2 q13 dup小鼠的任何行为改变，我们进行了一系列行为测试。尽管2 q13 dup小鼠在社会行为上没有表现出显著差异，但它们在自发交替行为和恐惧记忆上表现出缺陷。我们还进行了磁共振成像，以确认是否在这个位点的拷贝数增加影响神经解剖。2 q13 dup小鼠的小脑旁小叶有减少的趋势。这是人类2 q13重复的遗传小鼠模型的首次报道。
Duplications of human chromosome 2q13 have been reported in patients with neurodevelopmental disorder including autism spectrum disorder. Nephronophthisis‐1 (NPHP1) was identified as a causative gene in the minimal deletion on chromosome 2q13 for familial juvenile type 1 nephronophthisis and Joubert syndrome, an autosomal recessive neurodevelopmental disorder characterized by a cerebellar and brain stem malformation, hypotonia, developmental delay, ataxia, and sometimes associated with cognitive impairment. NPHP1 encodes a ciliary protein, nephrocystin‐1, which is expressed in the brain, yet its function in the brain remains largely unknown. In this study, we generated bacterial artificial chromosome‐based transgenic mice, called 2q13 dup, that recapitulate human chromosome 2q13 duplication and contain one extra copy of the Nphp1 transgene. To analyze any behavioral alterations in 2q13 dup mice, we conducted a battery of behavioral tests. Although 2q13 dup mice show no significant differences in social behavior, they show deficits in spontaneous alternation behavior and fear memory. We also carried out magnetic resonance imaging to confirm whether copy number gain in this locus affects the neuroanatomy. There was a trend toward a decrease in the cerebellar paraflocculus of 2q13 dup mice. This is the first report of a genetic mouse model for human 2q13 duplication.