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

Eleonora MainoOri ScottSamar Z RizviWing Suen ChanShagana VisuvanathanYoussif Ben ZablahHongbin LiAmeet S SengarMichael W SalterZhengping JiaEszter PosfaiRonald D CohnBin GuEvgueni A Ivakine
Published in: Disease models & mechanisms (2024)
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 harbouring a 160 kb tandem duplication encompassing Mecp2 and Irak1, representing the minimal disease-causing duplication, and the neighbouring genes Opnmw1 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.
Keyphrases
  • mouse model
  • crispr cas
  • genome wide
  • endothelial cells
  • cell proliferation
  • poor prognosis
  • risk assessment
  • gene expression
  • transcription factor
  • newly diagnosed
  • single cell
  • copy number