The ribosomal p70 S6 Kinase 1 (S6K1) has been implicated in the etiology of complex neurological diseases including autism, depression and dementia. Though no major gene disruption has been reported in humans in RPS6KB1, single nucleotide variants (SNVs) causing missense mutations have been identified, which have not been assessed for their impact on protein function. These S6K1 mutations have the potential to influence disease progression and treatment response. We mined the Simon Simplex Collection (SSC) and SPARK autism database to find inherited SNVs in S6K1 and characterized the effect of two missense SNVs, Asp14Asn (allele frequency = 0.03282%) and Glu44Gln (allele frequency = 0.0008244%), on S6K1 function in HEK293, human ES cells and primary neurons. Expressing Asp14Asn in HEK293 cells resulted in increased basal phosphorylation of downstream targets of S6K1 and increased de novo translation. This variant also showed blunted response to the specific S6K1 inhibitor, FS-115. In human embryonic cell line Shef4, Asp14Asn enhanced spontaneous neural fate specification in the absence of differentiating growth factors. In addition to enhanced translation, neurons expressing Asp14Asn exhibited impaired dendritic arborization and increased levels of phosphorylated ERK 1/2. Finally, in the SSC families tracked, Asp14Asn segregated with lower IQ scores when found in the autistic individual rather than the unaffected sibling. The Glu44Gln mutation showed a milder, but opposite phenotype in HEK cells as compared to Asp14Asn. Although the Glu44Gln mutation displayed increased neuronal translation, it had no impact on neuronal morphology. Our results provide the first characterization of naturally occurring human S6K1 variants on cognitive phenotype, neuronal morphology and maturation, underscoring again the importance of translation control in neural development and plasticity.

中文翻译：

---

人类p70 S6激酶1的N末端变体Asp14Asn增强翻译信号传导，在发育中的和成熟的神经元细胞中产生不同的作用。

核糖体p70 S6激酶1（S6K1）与复杂的神经系统疾病的病因有关，包括自闭症，抑郁症和痴呆症。尽管尚未在RPS6KB1中报道人类的主要基因破坏，但已鉴定出导致错义突变的单核苷酸变体（SNV），尚未评估其对蛋白质功能的影响。这些S6K1突变具有影响疾病进展和治疗反应的潜力。我们挖掘了Simon Simplex Collection（SSC）和SPARK自闭症数据库，以发现S6K1中的遗传SNV，并表征了两个错义SNV Asp14Asn（等位基因频率= 0.03282％）和Glu44Gln（等位基因频率= 0.0008244％）对S6K1功能的影响HEK293，人类ES细胞和原代神经元。在HEK293细胞中表达Asp14Asn导致S6K1下游靶标的基础磷酸化增加，并且从头翻译增加。该变体还显示出对特定S6K1抑制剂FS-115的反应迟钝。在人类胚胎细胞Shef4中，Asp14Asn在没有分化生长因子的情况下增强了自发性神经命运。除了增强的翻译，表达Asp14Asn的神经元显示受损的树突状树状化和磷酸化的ERK 1/2的水平增加。最后，在自闭症个体而不是未患病的同胞中，在追踪的SSC家族中，Asp14Asn的智商得分较低。与Asp14Asn相比，HEK细胞中的Glu44Gln突变显示出较轻但相反的表型。尽管Glu44Gln突变显示神经元翻译增加，它对神经元形态没有影响。我们的结果首次提供了自然存在的人类S6K1变体在认知表型，神经元形态和成熟度上的表征，再次强调了翻译控制在神经发育和可塑性中的重要性。