Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, a rare congenital anomaly syndrome characterized by intellectual disability, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and some visceral malformations is caused by de novo heterozygous mutations of the SON gene. The nuclear protein SON is involved in gene transcription and RNA splicing; however, the roles of SON in neural development remain undetermined. We investigated the effects of Son knockdown on neural development in mice and found that Son knockdown in neural progenitors resulted in defective migration during corticogenesis and reduced spine density on mature cortical neurons. The induction of human wild-type SON expression rescued these neural abnormalities, confirming that the abnormalities were caused by SON insufficiency. We also applied truncated SON proteins encoded by disease-associated mutant SON genes for rescue experiments and found that a truncated SON protein encoded by the most prevalent SON mutant found in ZTTK syndrome rescued the neural abnormalities while another much shorter mutant SON protein did not. These data indicate that SON insufficiency causes neuronal migration defects and dendritic spine abnormalities, which seem neuropathological bases of the neural symptoms of ZTTK syndrome. In addition, the results support that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.

中文翻译：

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击倒儿子是ZTTK综合征基因的小鼠同源物，会引起神经元迁移缺陷和树突棘异常。

Zhu-Tokita-Takenouchi-Kim（ZTTK）综合征是一种罕见的先天性异常综合征，其特征在于智力缺陷，脑畸形，面部畸形，肌肉骨骼异常以及一些内脏畸形是由SON基因的从头杂合突变引起的。核蛋白SON参与基因转录和RNA剪接。然而，SON在神经发育中的作用仍未确定。我们研究了Son敲低对小鼠神经发育的影响，发现在神经祖细胞中Son敲低导致了皮质形成过程中的缺陷迁移，并降低了成熟皮质神经元的脊柱密度。人类野生型SON表达的诱导挽救了这些神经异常，证实异常是由SON功能不足引起的。我们还应用了疾病相关突变SON基因编码的截短SON蛋白进行抢救实验，发现ZTTK综合征中最常见的SON突变体编码的截短SON蛋白可以挽救神经异常，而另一个短得多的突变SON蛋白则不能。这些数据表明SON功能不全会引起神经元迁移缺陷和树突棘异常，这似乎是ZTTK综合征神经症状的神经病理学基础。此外，结果支持ZTTK综合征的神经异常是由SON单倍体功能不全引起的，而与单元格功能或功能异常的突变类型无关。