Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism
Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism
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自闭症中发现的 16p11.2 病变模型的剂量依赖性表型
DOI：
10.1073/pnas.1114042108
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发表时间：
2011-10-11
影响因子：
11.1
通讯作者：
Mills, Alea A.
中科院分区：
文献类型：
--
作者：
Horev, Guy;Ellegood, Jacob;Mills, Alea A.
人类16p11.2的重复拷贝数变异（CNVs）与多种发育/神经认知综合征相关。特别是，16p11.2的缺失在自闭症、发育迟缓和肥胖患者中发现。缺失或重复的患者具有广泛的临床特征，携带相同缺失的兄弟姐妹通常具有不同的症状。为了以系统的方式研究16p11.2 CNVs的后果，我们使用染色体工程来产生具有对应于16p11.2的染色体区域的缺失的小鼠，以及具有相互重复的小鼠。这些16p11.2 CNV模型在基因表达、活力、脑结构和行为方面具有剂量依赖性变化。对于每种表型，缺失的后果比重复的后果更严重。特别值得注意的是，有一半的16p11.2缺失小鼠在出生后死亡;那些存活到成年的小鼠是健康和有生育能力的，但下丘脑发生了改变，并表现出“行为陷阱”表型--下丘脑外侧和黑质纹状体病变的啮齿动物的一种特定行为特征。这些发现表明，16p11.2 CNVs导致大脑和行为异常，为人类神经发育障碍提供了深入了解。
Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a "behavior trap" phenotype-a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.