An Irak1-Mecp2 tandem duplication mouse model for the study of MECP2 duplication syndrome

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 ( 'Mecp2 Dup'). ). The Mecp2 Dup mouse model recapitulates the genomic landscape of human MDS by harboring a 160 kb tandem duplication encompassing Mecp2 and Irak1, , representing the minimal disease-causing duplication, and the neighboring genes Opn1mw and Tex28. . The Mecp2 Dup model exhibits neuro-behavioral abnormalities, and an abnormal immune response to infection not previously observed in other mouse models, possibly owing to Irak1 overexpression. The Mecp2 Dup model thus provides a tool to investigate MDS disease mechanisms and develop potential therapies applicable to patients.