Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Genetics Neuroscience Article has an altmetric score of 8

GIGYF1 disruption associates with autism and impaired IGF-1R signaling

  • Text
  • PDF
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

×

Figure 3

KO and haploinsufficiency of Gigyf1 in the developing mouse brain results in autism-like behaviors.

Options: View larger image (or click on image) Download as PowerPoint
KO and haploinsufficiency of Gigyf1 in the developing mouse brain result...
(A) Three-chamber test. The time spent with object (O), stranger 1 (S1) and stranger 2 (S2) was compared. The preference indexes were compared. n = 21 (Gigyf1fl/fl), 19 (cHET), 20 (cKO). Statistical data were analyzed using 1-way ANOVA and 2-tailed Student’s t test. (B) Marble burying test. The percentage of marbles buried by each mouse was compared. Statistical data were analyzed using 1-way ANOVA. (C) Digging, rearing, and grooming test. The numbers of digging, rearing, and grooming incidences of the different groups of mice were compared. n = 20 (Gigyf1fl/fl), 19 (cHET), 19 (cKO). Statistical data were analyzed using 1-way ANOVA. (D) Elevated plus-maze test. The time and the total distance in open and closed arms were compared. n = 19 (Gigyf1fl/fl), 19 (cHET), 20 (cKO). Statistical data were analyzed using 1-way ANOVA. (E) Open field test. The total distance and center duration were compared. n = 21 (Gigyf1fl/fl), 19 (cHET), 19 (cKO). Statistical data were analyzed using 1-way ANOVA. (F) Light-dark box test. The preference indexes to dark box were compared. n = 19 (Gigyf1fl/fl), 19 (cHET), 20 (cKO). Statistical data were analyzed using 1-way ANOVA. (G) Morris water maze test. The escape latency in the learning phase, the number of exact crossings over the previously hidden platform in the probe phase, the swim speed, and the time and distance in the target quadrant in the probe phase were compared. n = 22 (Gigyf1fl/fl), 19 (cHET), 20 (cKO). Statistical data were analyzed using 1-way and 2-way ANOVA. (H) Novel-object recognition test. Total exploration time and discrimination index were compared. n = 20 (Gigyf1fl/fl), 18 (cHET), 19 (cKO). Statistical data were analyzed using 1-way ANOVA and 2-tailed Student’s t test. All data are represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. cHET, Gigyf1f/w-CreNestin; cKO,Gigyf1fl/fl-CreNestin.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Posted by 6 X users
On 1 Facebook pages
12 readers on Mendeley
See more details