biostudies-literatureChen GHunan Provincial grantsNIDDK NIH HHSNIMH NIH HHSNational Natural Science Foundation of ChinaNational Institutes of Healthe159806https://www.ebi.ac.uk/biostudies/studies/S-EPMC9525121biostudies-literatureUnknown132(19)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.The Journal of clinical investigationGIGYF1 disruption associates with autism and impaired IGF-1R signaling.PMC9525121R56 DK002001NIH R01MH101221no. 2021JJ10070,no. 2019RS2005,no. 2019SK1010,no. 2021DK2001,no. 2019SK1015,no. 2021SK1010,no. 2021YFA0805202,no. 2019SK2051no. 81871079,no. 8173000779,no. 81671122,R01 MH101221R01 DK002001Fernandez-Jaen ACutcutache IKurtz-Nelson ECHu ZKing SDJiang QHan YBernier RAZhang QRamos LLBrooks DXia KSebastian JGuo HJia XIdleburg MJAlvarez SHua YHoekzema KSymonds JDTan JChen GYuan LSantos MLSEarl RKYu BMartin DMZhang XEichler EETan SClark RPan QLuo SMadan-Khetarpal SfalseGIGYF1 disruption associates with autism and impaired IGF-1R signaling.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.2022-01-01T00:00:00Z2022 Oct2024-11-07T00:31:26.687Z2024-11-07T00:31:26.687ZS-EPMC95251213591718610.1172/JCI159806