Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. An excess of likely gene-disruptive (LGD) mutations in GIGYF1 was implicated in ASD. Here, we report that GIGYF1 is the second-most mutated gene among known ASD high–confidence risk genes. We investigated the inheritance of 46 GIGYF1 LGD variants, including the highly recurrent mutation c.333del:p.L111Rfs*234. Inherited GIGYF1 heterozygous LGD variants were 1.8 times more common than de novo mutations. Among individuals with ASD, cognitive impairments were less likely in those with GIGYF1 LGD variants relative to those with other high-confidence gene mutations. Using a Gigyf1 conditional KO mouse model, we showed that haploinsufficiency in the developing brain led to social impairments without significant cognitive impairments. In contrast, homozygous mice showed more severe social disability as well as cognitive impairments. Gigyf1 deficiency in mice led to a reduction in the number of upper-layer cortical neurons, accompanied by a decrease in proliferation and increase in differentiation of neural progenitor cells. We showed that GIGYF1 regulated the recycling of IGF-1R to the cell surface. KO of GIGYF1 led to a decreased level of IGF-1R on the cell surface, disrupting the IGF-1R/ERK signaling pathway. In summary, our findings show that GIGYF1 is a regulator of IGF-1R recycling. Haploinsufficiency of GIGYF1 was associated with autistic behavior, likely through interference with IGF-1R/ERK signaling pathway.

中文翻译：

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GIGYF1 破坏与自闭症和 IGF-1R 信号受损有关

自闭症谱系障碍 (ASD) 代表一组具有强烈遗传成分的神经发育表型。GIGYF1中过多的可能的基因破坏性（LGD）突变与 ASD 有关。在这里，我们报告GIGYF1是已知 ASD 高置信度风险基因中突变第二多的基因。我们研究了 46 个GIGYF1 LGD 变体的遗传，包括高度复发的突变 c.333del:p.L111Rfs*234。遗传的GIGYF1杂合 LGD 变体比从头突变常见 1.8 倍。在患有 ASD 的个体中，与具有其他高置信度基因突变的个体相比，具有GIGYF1 LGD 变异的个体认知障碍的可能性较小。使用Gigyf1在条件 KO 小鼠模型中，我们发现发育中的大脑中的单倍体不足会导致社交障碍而没有明显的认知障碍。相比之下，纯合小鼠表现出更严重的社交障碍和认知障碍。小鼠Gigyf1缺乏导致上层皮质神经元数量减少，伴随神经祖细胞增殖减少和分化增加。我们发现 GIGYF1 调节 IGF-1R 循环到细胞表面。GIGYF1的KO导致细胞表面IGF-1R水平降低，破坏了IGF-1R/ERK信号通路。总之，我们的研究结果表明 GIGYF1 是 IGF-1R 再循环的调节剂。GIGYF1的单倍体不足与自闭症行为有关，可能是通过干扰 IGF-1R/ERK 信号通路。