Two de novo likely gene-disruptive/protein-truncating variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). Additional de novo likely gene-disruptive/protein-truncating variants in GIGYF1 were identified in ASD probands from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium (Satterstrom et al., 2020); six protein-truncating variants in this gene were also observed in case samples from the Danish iPSYCH study in Satterstrom et al., 2020. Furthermore, independent TADA analyses in Feliciano et al., 2019 and Satterstrom et al., 2020 identified GIGYF1 as an ASD candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified GIGYF1 as a gene reaching exome-wide significance (P < 2.5E-06). Analysis of whole-exome sequencing or whole-genome sequencing data from the SPARK cohort and the Simons Simplex Collection in Chen et al., 2022 identified a significant de novo enrichment (P<2.7E-12) and significant transmission disequilibrium (P<1E-05) of GIGYF1 heterozygous likely gene-disruptive (LGD) variants in these two cohorts; a recurrent LGD variant in GIGYF1 (c.332del;p.Leu111ArgfsTer234) that was detected in 23 ASD individuals from 20 families or singleton cases and shown experimentally to result in abnormal cellular localization in mouse primary cultured neurons also showed significant de novo enrichment (P=0.0004) and significant transmission disequilibrium (P=0.03). Additional mouse model studies in Chen et al., 2022 demonstrated Gigyf1 conditional knockout mice exhibited social impairments without significant cognitive impairments and a reduction of upper layer cortical neurons accompanied by decreased proliferation and increased differentiation of neural progenitor cells.
Molecular Function
The protein encoded by this gene may act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling and may increase IGF1 receptor phosphorylation under IGF1 stimulation as well as phosphorylation of IRS1 and SHC1 (by similarity).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Gigyf1 haploinsufficiency in the developing brain leads to social impairments without significant cognitive impairments, but homozygous mice showed more severe social disability as well as cognitive impairments. Gigyf1 deficiency in mice also leads to a reduction of upper layer cortical neurons accompanied by decreased proliferation and increased differentiation of neural progenitor cells. Gigyf1 is shown to be a regulator of IGF-1R recycling and interferes with IGR-1R/ERK signaling pathway.
References
Type
Title
Author, Year
Primary
GIGYF1 disruption associates with autism and impaired IGF-1R signaling
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Floxed mice(Gigyf1^flox/flox) were generated mice with conditional alleles carrying loxP sites in introns 1 and 9 by CRISPR/Cas9 targeting strategy. The Gigyf1^flox/flox mice were crossed with Nestin-Cre mice to generate Gigyf1^flox/+-CreNestin (conditional heterozygote) and Gigyf1^flox/flox-CreNestin (conditional knockout) mice.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C56BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: GemPharmatech, Co., Ltd.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Floxed mice(Gigyf1^flox/flox) were generated mice with conditional alleles carrying loxP sites in introns 1 and 9 by CRISPR/Cas9 targeting strategy. The Gigyf1^flox/flox mice were crossed with Nestin-Cre mice to generate Gigyf1^flox/+-CreNestin (conditional heterozygote) and Gigyf1^flox/flox-CreNestin (conditional knockout) mice.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C56BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: GemPharmatech, Co., Ltd.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Gigyf1 conditional knockout (cKO) allele was generated using the CRISPR/Cas9 system to flank the 10th-24th exons by loxP sites. Constitutive Gigyf1 KO mice were generated by crossing mice carrying the cKO allele with CMV-Cre mice.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Huazhong University of Science and Technology; Biocytogen, Beijing, China
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Gigyf1 conditional knockout (cKO) allele was generated using the CRISPR/Cas9 system to flank the 10th-24th exons by loxP sites. Constitutive Gigyf1 KO mice were generated by crossing mice carrying the cKO allele with CMV-Cre mice.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Huazhong University of Science and Technology; Biocytogen, Beijing, China
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Gigyf1 conditional knockout (cKO) allele was generated using the CRISPR/Cas9 system to flank the 10th-24th exons by loxP sites. Conditional Gigyf1 KO mice with ablation of the gene in excitatory neurons mice were generated by crossing mice carrying the cKO allele with NEX-Cre mice (MGI:2668659).
Allele Type: Conditional knockout
Strain of Origin: Not specified; (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: Not specified; R1
Mutant ES Cell Line: Model Source: Huazhong University of Science and Technology; Klaus-Armin Nave lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Gigyf1 conditional knockout (cKO) allele was generated using the CRISPR/Cas9 system to flank the 10th-24th exons by loxP sites. Conditional Gigyf1 KO mice with ablation of the gene in inhibitory neurons mice were generated by crossing mice carrying the cKO allele with GAD2-Cre mice (MGI:4418713).
Allele Type: Conditional knockout
Strain of Origin: Not specified; (C57BL/6 x 129S4/SvJae)F1
Genetic Background: C57BL/6J
ES Cell Line: Not specified; v6.5
Mutant ES Cell Line: Model Source: Huazhong University of Science and Technology; Neuroscience Blueprint cre
Description: There were fewer upper layer neurons labeled with markers Satb2 and Brn2 in both the conditional heterozygous and conditional knockout cortex compared to the cortex of controls; but there was no significant difference in the numbers of deeper layer neurons including Tbr1+ and Ctip2+ cells in conditional heterozygous and conditional knockout cortex.
Exp Paradigm: Satb2, Brn2, Tbr1, Ctip2
Description: The numbers of Pax6+ radial glial cells and Tbr2+ intermediate progenitor cells were decreased in both the conditional heterozygous and conditional knockout mice cortex, indicating a decreased pool of neural progenitor cells from Gigyf1 deficiency.
Exp Paradigm: Pax6, Tbr2
Description: EdU+ cells were decreased in both conditional heterozygous and conditional knockout cortex at E14.5. However, the Pax6+Edu+/Pax6+ cells were increased in conditional knockout cortex; The duration of S phase (Ts) of conditional heterozygous and conditional knockout neural progenitor cells (NPCs) are significantly longer when compared to the control NPCs. Increases of Ts are also observed in conditional heterozygous and conditional knockout embryos at E12.5.
Description: The differentiation of neural progenitor cells in conditional heterozygous and conditional knockout cortex was accelerated compared with the cortex of the controls.
Exp Paradigm: Pulse-labeling experiments with Edu
Description: Conditional heterozygous mice spent more time with social targets compared to an inanimate object. However, the social interaction preference index of conditional heterozygous mice was significantly lower than controls.
Description: There was no difference in time spent between the novel and familiar mouse in both conditional heterozygous and conditional knockout mice.
Description: pIgf-1r and pErk levels are significantly diminished in the cortical lysates of both conditional heterozygous and conditional knockout mice compared to control mice.
Description: Immunohistochemistry of pErk reveals decreased fluorescence intensity of pErk in the cortex of conditional heterozygous and conditional knockout mice.
Description: The numbers of Pax6+ radial glial cells and Tbr2+ intermediate progenitor cells were decreased in both the conditional heterozygous and conditional knockout mice cortex, indicating a decreased pool of neural progenitor cells from Gigyf1 deficiency.
Exp Paradigm: Pax6, Tbr2
Description: Edu+ cells were decreased in both conditional heterozygous and conditional knockout cortex at E14.5. However, the Pax6+Edu+/Pax6+ cells were increased in conditional knockout cortex. The duration of S phase (Ts) of conditional heterozygous and conditional knockout neural progenitor cells (NPCs) are significantly longer when compared to the control NPCs. Increases of Ts are also observed in conditional heterozygous and conditional knockout embryos at E12.5.
Description: The differentiation of neural progenitor cells in conditional heterozygous and conditional knockout cortex was accelerated compared with the cortex of the controls.
Description: There were fewer upper layer neurons labeled with markers Satb2 and Brn2 in both the conditional heterozygous and conditional knockout cortex compared to the cortex of controls; but there was no significant difference in the numbers of deeper layer neurons including Tbr1+ and Ctip2+ cells in conditional heterozygous and conditional knockout cortex.
Exp Paradigm: Satb2, Brn2, Tbr1, Ctip2
Description: There was no difference in time spent between the novel and familiar mouse in both conditional heterozygous and conditional knockout mice.
Description: Conditional knockout mice showed a decrease in the total time exploring and in the discrimination index to the non-familiar object compared to control mice.
Description: pIgf-1r and pErk levels are significantly diminished in the cortical lysates of both conditional heterozygous and conditional knockout mice compared to control mice.
Description: Immunohistochemistry of pErk reveals decreased fluorescence intensity of pErk in the cortex of conditional heterozygous and conditional knockout mice.
Description: RNA sequencing identified 4 upregulated genes and 14 downregulated genes that are shared between homozygous, heterozygous knockout mice and zebrafish models compared to the respective controls. Homozygous knockouts show upregulation of 343 genes, and downregulation of 560 genes.
Description: Heterozygous Gigyf1 knockout mice harbor a higher percentage of Slc17a7-positive(Vglut1-positive) excitatory neurons in the CA2-CA3 region.
Description: The density of NeuN-positive neurons in the CA2 region was significantly increased in Gigyf1 heterozygous knockout mice. No change in NeuN-positive neuron density was observed in CA1, CA3 or DG.
Exp Paradigm: NeuN
Description: Heterozygous Gigyf1 knockout mice displayed repetitive behavior with excessive grooming, measured by number of grooming bouts and time spent grooming.
Description: RNA sequencing identified 4 upregulated genes and 14 downregulated genes that are shared between homozygous, heterozygous knockout mice and zebrafish models compared to the respective controls. Heterozygous knockouts show upregulation of 249 genes, and downregulation of 468 genes.
Description: The inhibitory neuron specific knockout of Gigyf1 does not show a deficit in social approach, but an increase in preference for the stranger mouse.
Description: The inhibitory neuron specific knockout of Gigyf1 shows elevated anxiety levels with decreased time spent in the center of the open field.
Description: The inhibitory neuron specific knockout of Gigyf1 exhibits a significant impairment in cognitive performance in the novel object recognition test.
