2026-05-20 韓国基礎科学研究院（IBS）
＜関連情報＞
- https://www.ibs.re.kr/cop/bbs/BBSMSTR_000000000738/selectBoardArticle.do?nttId=26701&pageIndex=1&searchCnd=&searchWrd=#toggle
- https://www.nature.com/articles/s41380-026-03646-9
ホモ接合型CHD8変異はASD表現型を増強し、性差を弱める Homozygous CHD8 mutation intensifies ASD phenotypes and attenuates sex differences
Jinkyeong Kim,Seungjoon Lee,Eunkyu Hwang,Hwajin Jung,Chanhee Lee,Sang-Han Choi,Sooyeon Lee,Seongbin Kim,Heera Moon,Jisoo Kim,Gina Lee,Yong Gyu Kim,Soogeun Shin,Hyojin Kang,Se Jin Kim,Heon Yung Gee,Seong-Gi Kim,Eunee Lee & Eunjoon Kim
Molecular Psychiatry Published:09 May 2026
DOI:https://doi.org/10.1038/s41380-026-03646-9
Abstract
CHD8 is a chromatin remodeler implicated in autism spectrum disorders (ASD) and multiple neurodevelopmental disorders, yet heterozygous Chd8-mutant mouse lines often exhibit only mild ASD-related phenotypes, leaving its role unclear. Because a complete knockout of Chd8 causes embryonic lethality, we generated viable homozygous Chd8-mutant mice carrying the human CHD8-Asn2373LysfsX2 mutation using a hybrid (C57BL6/J × 129/Sv) genetic background. Compared to heterozygous Chd8+/N2373K mice, the homozygous Chd8N2373K/N2373K mice showed more robust phenotypes, including increased ASD-related behaviors and brain volume, decreased cerebral blood volume/flow, brain rhythms, and synaptic transmission, and ASD-related transcriptomic changes. Notably, while Chd8+/N2373K mice on a pure background predominantly displayed behavioral deficits in males, the homozygous mutants in the hybrid background exhibited more pronounced female phenotypes, suggesting the interaction of genetic background and mutation strength. A direct comparison of Chd8+/N2373K and Chd8N2373K/N2373K mice on the same hybrid background across brain volume, cerebral blood flow, neuronal firing, synaptic transmission, and transcriptome revealed a gene dosage-dependent attenuation of sexual dimorphic phenotypes that varied by developmental stage and brain region. Transcriptomic analyses further implicated pathways related to synaptic function, RNA splicing, and mitochondrial activity in mediating differences in male–female protection and susceptibility. Thus, a homozygous Chd8 mutation not only intensifies ASD-related traits but can also diminish typical sex-specific severity patterns, uncovering a novel link between mutation strength and sexual dimorphism in ASD.
