Kyushu University clarifies a molecular mechanism behind pathogenesis of ASD using mouse experiments

A research group led by lead Professor Keiichi Nakayama and Graduate Student Taichi Shiraishi of Kyushu University, Professor Masaaki Nishiyama of Kanazawa University, Professor Tsuyoshi Miyakawa of Fujita Health University, and Professor Tsuyoshi Shirai of Nagahama Institute of Bio-Science and Technology has announced the clarification of a new molecular mechanism behind the pathogenesis of autism spectrum disorder (ASD). They characterized and classified missense mutations on the CHD8 gene in patients with autism spectrum disorder by applying six prediction scores. Introduction of high-score mutations into stem cells and mice confirmed decreased expression of nerve-related genes and impaired differentiation into neurons. The findings are expected to contribute to the development of therapeutic methods and the prediction of the risk of developing ASD. The results were published in the March 5 issue of the international academic journal Molecular Psychiatry.

ASD is a neurodevelopmental disorder characterized primarily by "impaired interpersonal communication" and "markedly limited range of activities and interests," for which no radical treatment or accurate diagnostic methods have been established. A recent large-scale genetic mutation search in patients with the disorder has identified CHD8 as the most commonly mutated gene. Currently, there are 291 CHD8 gene mutations reported in patients with ASD, and many studies have focused on reduced CHD8 protein levels. Meanwhile, this decrease has been found to be caused by genetic mutations such as nonsense mutations and frameshift mutations, and missense mutations resulting in only a single amino acid change accounts for the majority of CHD8 gene mutations.

The research group aimed to analyze how missense mutations are involved in the development of autism spectrum disorder. They first characterized all reported CHD8 gene missense mutations using the six predictive scores to extract the characteristics for classification and found that the CHD8 gene missense mutations could be divided into two major groups: those with high scores and those with low scores.

To shed light on the mechanism by which these mutations contribute to the development of ASD, they introduced several representative mutations into stem cells and mice and analyzed the effects. The results showed that stem cells transfected with high-score mutations expressed nerve-related genes at reduced levels and that their differentiation into nerve cells was hindered.

Mice with these high-score mutations also showed ASD-like behavioral abnormalities, such as increased anxiety and abnormal social behavior. Among the mutations that caused the disorder-like behavior in mice, some were accompanied by impaired activity of the CHD8 protein, whereas others were not. This indicates that high-score mutations may cause ASD through diverse molecular mechanisms. In contrast, all low-score mutations had no effects on protein activity, cell differentiation, or mouse behavior. This indicates that the currently reported CHD8 gene mutations include some that are not directly involved in the development of ASD. The scores employed in this study are expected to improve risk prediction and accuracy of diagnosis.

Nakayama said, "While many psychiatric disorders have many genetic abnormalities involved in pathogenesis, some cases of ASD are known to be attributable to a single genetic abnormality. The CHD8 gene has been found to be the most frequently mutated gene in autism spectrum disorder. We were the first in the world to report that CHD8 gene-deleted mice exhibit ASD-like behavior (Nature 2016). However, most CHD8 gene abnormalities in humans are not deletions but minute point mutations, and it remained unclear how such minute abnormalities can cause ASD. In the present study, we were able to clarify the mechanism and get closer to the cause of the disorder. We believe that these findings will contribute to the development of treatments in the future."

Journal Information
Publication: Molecular Psychiatry
Title: The complex etiology of autism spectrum disorder due to missense mutations of CHD8
DOI: 10.1038/s41380-024-02491-y