CHD2関連発達遅延モデルにおける行動およびてんかん表現型

Heterozygous loss-of-function mutations in the CHD2 gene, encoding chromodomain helicase DNA-binding protein 2, are associated with severe childhood onset epilepsy, global developmental delay, and autistic features. Animal models that accurately recapitulate human phenotypes are crucial for understanding rare neurodevelopmental disorders and developing novel treatments. However, such a model for CHD2-related disorders has been missing.

We performed behavioral, electrographic, epileptic, and transcriptomic analyses to characterize a mouse model harboring a frameshift truncating mutation in the Chd2 gene (Chd2^WT/m and Chd2^m/m mice) on the 129X1/SvJ background.

The genetic background altered the severity of disease-related phenotypes, such that crossing the mice from the C57BL/6J onto the 129X1/SvJ background uncovered neurodevelopmental phenotypes. On the 129X1/SvJ background, Chd2^m/m mice exhibited growth retardation, and both Chd2^WT/m and Chd2^m/m mice showed motor deficits, including clasping behavior and impaired balance on a rotating rod. Autistic like features included reduced nest-building abilities in Chd2^m/m mice, whereas increased repetitive like behavior in the marble-burying test and altered social behavior were observed in Chd2^WT/m mice. Electrocorticographic analysis revealed a global reduction in the power of background oscillations in both Chd2^WT/m and Chd2^m/m mice, along with increased susceptibility to 4-aminopyridine-induced seizures. Transcriptomic analysis identified upregulation of Kcnj11 mRNA in Chd2^WT/m and Chd2^m/m mice on the 129X1/SvJ background.

This mouse model recapitulates key phenotypes observed in CHD2 patients, providing a valuable platform to study the molecular basis and potential treatment strategies for this intractable disorder.