A Cas9-fusion proximity-based approach generates anIrak1-Mecp2tandem duplication mouse model for the study of MeCP2 duplication syndrome

Abstract

AbstractMECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of theMECP2locus and its surrounding genes, includingIRAK1. Current MDS mouse models involve transgenic expression ofMECP2only, limiting their applicability to the study of the disease. Herein, we show that an efficient and precise CRISPR/Cas9 fusion proximity-based approach can be utilized to generate anIrak1-Mecp2tandem duplication mouse model. TheMecp2 Dupmodel displays a neurological phenotype in keeping with MDS and demonstrates an abnormal immune response to infection not previously observed in other mouse models, possibly stemming from concurrentIrak1overexpression. TheMecp2 Dupmouse line thus provides an innovative tool to investigate disease mechanisms and potential therapeutic development.