GIGYF1 disruption associates with autism and impaired IGF-1R signaling
Guodong Chen, … , Kun Xia, Hui Guo
Guodong Chen, … , Kun Xia, Hui Guo
Published August 2, 2022
Citation Information: J Clin Invest. 2022;132(19):e159806. https://doi.org/10.1172/JCI159806.
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GIGYF1 disruption associates with autism and impaired IGF-1R signaling

Abstract

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.

Authors

Guodong Chen, Bin Yu, Senwei Tan, Jieqiong Tan, Xiangbin Jia, Qiumeng Zhang, Xiaolei Zhang, Qian Jiang, Yue Hua, Yaoling Han, Shengjie Luo, Kendra Hoekzema, Raphael A. Bernier, Rachel K. Earl, Evangeline C. Kurtz-Nelson, Michaela J. Idleburg, Suneeta Madan-Khetarpal, Rebecca Clark, Jessica Sebastian, Alberto Fernandez-Jaen, Sara Alvarez, Staci D. King, Luiza L.P. Ramos, Mara Lucia S.F. Santos, Donna M. Martin, Dan Brooks, Joseph D. Symonds, Ioana Cutcutache, Qian Pan, Zhengmao Hu, Ling Yuan, Evan E. Eichler, Kun Xia, Hui Guo

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Figure 2

Phenotypic correlation of GIGYF1 heterozygous LGD mutations.

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Phenotypic correlation of GIGYF1 heterozygous LGD mutations. (A) Compari...
(A) Comparison of the SCQ and RBS-R scores in children with ASD with GIGYF1 LGD variants and all children with ASD in SPARK. (B) Comparison of cognitive impairment (CI) occurrence rate among children with ASD with GIGYF1 LGD variants, children with ASD with LGD variants in known high-confidence genes, and all SPARK children with ASD. (C) Comparison of the frequency of behavior problems, developmental delays, and neuropsychiatric problems between children with ASD with and without GIGYF1 LGD variants. The details of specific phenotype items for each phenotype group in the plot are described in Supplemental Table 9. (D) Comparison of developmental delay occurrence rate among children without ASD with GIGYF1 LGD variants and all children without ASD in SPARK. (E) Down sampling analysis of SRS t score in siblings without ASD from the SSC cohort. (F) Comparison of the frequency of behavior problems, developmental delay, and neuropsychiatric problems between nonASD parents with and without GIGYF1 LGD variants. The details of specific phenotype items for each phenotype group in the plot are described in Supplemental Table 9.