JCI Guo Hui/Xia Kun/Tan Jieqiong collaborated to reveal the genetic and molecular mechanisms by which GIGYF1 is involved in autism risk

Autism Spectrum Disorder (ASD) is a class of neurodevelopmental disorders that occur early in childhood development with core symptoms of deficits in social interaction and communication and repetitive stereotyped behaviors
.
In addition to the core symptoms, individuals with ASD often have other symptoms
.
The severity of core symptoms and the type and extent of comorbidities can vary widely between individuals with ASD, exhibiting a high degree of clinical phenotypic heterogeneity
.

Over the past decade, with the rapid development of sequencing technology, more than 300 high-confidence ASD risk genes have been identified
.
Most of these genes are found from the perspective of new mutations
(carried by affected individuals, not by parents).
As a result, most of the disease-related risk variants in these genes are extremely rare
.
Currently, the genetic patterns, clinical phenotypic associations, and molecular mechanisms involved in the occurrence of ASD in most known ASD risk genes in the ASD population are still unknown, including GIGYF1
.

GIGYF1 was first identified as being associated with ASD in 2014
.
In 2508 ASD families from the US SSC cohort, 2 families carrying GIGYF1 were found to have a new dysfunctional variant [1
].
In 2020, through the analysis of full-exon sequencing data from more than 6,000 ASD families (including previously published data), a total of 4 cases of new GIGYF1 heterozygous deletion variants were found, and for the first time, the heterozygous deletion variation of GIGYF1 was shown to be associated with ASD risk from genome-wide significance levels relatively strictly[2].

Nevertheless, the genetic pattern of GIGYF1 in ASD families, the association of clinical phenotypes, and its molecular mechanisms involved in neurodevelopment and the occurrence of ASD remain unknown
.

On October 3, 2022, J Clin Invest officially published a research paper entitled GIGYF1 disruption associates with autism and impaired IGF-1R signaling [3] in the form of a long article (the paper was published in JCI on August 3 in-press preview）
。 J Clin Invest also distributed a commentary entitled GIGYF1-disturbed IGF-1R recycling: a potential contributor to autism spectrum disorder pathogenesis?[4]
at the same time 。 The review notes that these studies strongly support the role of the GIGYF1-1R/ERK pathway in the occurrence of ASD; Added important insights into the complex genetic structure and biological mechanisms of ASD etiology; It also provides the possibility
of assessing and preventing ASD associated with GIGYF1 deficiencies.


To fully understand the genetic patterns and mechanisms of GIGYF1's involvement in autism risk, the authors first analyzed genome-wide or whole-exome sequencing data
from more than 30,000 ASD families/individuals from SPARK and SSC (two ASD research cohorts funded by the Simons Foundation of America).
The GIGYF1 heterozygous deletion mutation was found to rank second
in the frequency of mutations among the known high-confidence risk genes for ASD.
Of particular note is the author's findings of the same frequency variation, c.
333del: p.
L111Rfs*234, across 20 families (proportion of the total ASD population: 0.
6‰
).
Although rare, this variant can serve as a potential biological marker
for early warning of ASD risk.

Previous findings focused on new variants
in GIGYF1.
In this study, the authors found that the heterozygous deletion variant of GIGYF1 inherited by parents was 1.
8 times higher than that of the new variant, and that the hereditary variant had a significant transmission imbalance
in the ASD lineage.
This result underscores the importance of analysis of rare genetic variants in autism high-confidence genes
.

Phenotyping analysis found that individuals with ASD who carried the GIGYF1 mutation had comparable severity to the core symptoms with the average of the ASD population
.
However, the authors found that individuals carrying the GIGYF1 mutation had significantly lower rates of intellectual disability than individuals carrying other known high-risk gene variants, and possibly even lower than the incidence of intellectual disability in the ASD population (requiring larger sample validation).

These results suggest that insufficient monodosage of GIGYF1 may have a lower
effect on intelligence than other high-risk genes for ASD.
This suggests that GIGYF1 may be a better candidate gene for studying the core phenotype of ASD
.
It is also worth noting that siblings or parents who carry the GIGYF1 mutation but are not diagnosed with ASD show poorer social skills and more developmental and behavioral problems
.

Using a mouse model of Gigyf1 neurological condition knockout, the authors found that insufficient monodosage of Gigyf1 resulted in significant social impairment and certain repetitive stereotyped behaviors, but did not exhibit significant differences in cognitive impairment
.
Gigyf1 knockout, on the other hand, leads to more severe phenotypes
such as social and cognitive impairment.
The authors also found that in the early cortical neurogenesis, the deletion of Gigyf1 leads to a decrease in the proliferation of neuroprecursor cells and a prolongation of the S phase of the cell cycle as well as a decrease
in superficial cortical neurons.
These results suggest that Gigyf1 may affect the proliferation of neural premise cells by influencing the cell cycle, which in turn leads to a decline in
the number of cortical neurons.

So, how does the loss of GIGYF1 lead to the neurodevelopmental disorders and autism-related phenotypes described above? In the exploration of molecular mechanisms, the authors found that GIGYF1 may be a regulator of IGF-1R cycle recovery
.
Insufficient or absent haploscale doses of GIGYF1 lead to abnormal intracellular recycling of IGF-1R and decreased
activity of the ERK signaling pathway downstream of IGF-1R.
Molecular changes in the IGF-1R axis were also validated
in GIGYF1 knockout mouse model bodies.
Based on the above findings, the authors believe that the functional loss of GIGYF1 affects the recycling of IGF-1R, resulting in a decrease in the level of IGF-1R on the membrane, thereby affecting the downstream ERK signaling pathway activity
.
The disturbance of the molecular signaling pathway may cause abnormal proliferation and differentiation of neural precursor cells in the early cortical process, which in turn causes disorders of cortical development
.

Graphic Abstract Chen Guodong, Yu Bin, Tan Senwei, and associate researcher Tan Jieqiong, doctoral students of the Medical Genetics
Research Center of Central South University, are the co-first authors
of the paper.

Guo Hui's research group and Xia Kun's research group have long-term cooperation
in the research direction of genetic basis and pathogenesis of autism.
The team has established research systems and platforms
in human and medical genetics, genome and bioinformatics, cell and molecular biology, and neurobiology.
In recent years, he has published a series of research papers as a corresponding author in academic journals such as Sci Adv (2 papers), J Clin Invest, Nat Commun, Mol Psychiatry (2 papers
), AJHG, NAR, Circulation, Brain and so on.
The team has long hired postdocs
.

Resume delivery (interested parties should send personal resume and other materials to): https://jinshuju.
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Maker: Eleven

References

1.
Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al.
The contribution of de novo coding mutations to autism spectrum disorder.
Nature.
2014; 515(7526):216-21.
2.
Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An JY, et al.
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.
Cell.
2020; 180(3):568-84 e233.
Chen G, Yu B, Tan S, Tan J, Jia X, Zhang Q, et al.
.
GIGYF1 disruption associates with autism and impaired IGF-1R signaling.
J Clin Invest.
2022 132(19):e159806.
4.
Xing M, Zhang Q, Song W.
GIGYF1-disturbed IGF-1R recycling: a potential contributor to autism spectrum disorder pathogenesis? J Clin Invest.
2022；132(19):e163553.
‍

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