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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Research Article Genetics Neuroscience

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 1

Pattern, distribution, and inheritance of GIGYF1 heterozygous LGD mutations in humans.

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Pattern, distribution, and inheritance of GIGYF1 heterozygous LGD mutati...
(A) Mutation pattern of GIGYF1 likely gene-disruptive variants (LGD variants) identified in SPARK and/or SSC cohorts (above) and through GeneMatcher (below) on a gene model. (B) Ranked mutation frequency of LGD variants in 102 high-confidence genes identified in Satterstrom et al. (7). (C) Pedigrees with the recurrent variant p.L111Rfs*234 identified in the SPARK and SSC cohorts. +/+, WT; +/–, heterozygous. Families with untransmitted or de novo GIGFY1 LGD variants only in unaffected family members are indicated by the square outline. Solid circles or squares represent individuals with an ASD diagnosis. Numbers above each pedigree are SPARK family designations; red +/- indicate individuals with mutations. (D) The recurrent LGD locus p.L111Rfs*234 shows abnormal localization in mouse primary-cultured neurons. The WT plasmid is mainly located in the cytoplasm; however, the mutant plasmid is exclusively located in the nuclei. Scale bars: 10 μm, 2 μm for zoom image.