A Cas9-fusion proximity-based approach generates an Irak1-Mecp2 tandem duplication mouse model for the study of MeCP2 duplication syndrome.

Abstract

MECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of the MECP2 locus and its surrounding genes, including IRAK1. Current MDS mouse models involve transgenic expression of MECP2 only, 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 an Irak1-Mecp2 tandem duplication mouse model. The Mecp2 Dup model 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 concurrent Irak1 overexpression. The Mecp2 Dup mouse line thus provides an innovative tool to investigate disease mechanisms and potential therapeutic development.