An <i>Irak1-Mecp2</i> tandem duplication mouse model for the study of <i>MECP2</i> duplication syndrome-Reference-Cited by-同舟云学术

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

Published:2024-07-01 Issue:7 Volume:17 Page:
ISSN:1754-8403
Container-title:Disease Models & Mechanisms
language:en
Short-container-title:

Author:

Maino Eleonora¹²^ORCID,Scott Ori¹³,Rizvi Samar Z.¹²^ORCID,Chan Wing Suen¹^ORCID,Visuvanathan Shagana¹,Zablah Youssif Ben⁴⁵,Li Hongbin⁵,Sengar Ameet S.⁵,Salter Michael W.⁴⁵,Jia Zhengping⁴⁵,Rossant Janet²⁶^ORCID,Cohn Ronald D.¹²³⁷,Gu Bin⁸⁹^ORCID,Ivakine Evgueni A.¹²⁴^ORCID

Affiliation:

1. the Hospital for Sick Children 1 Program in Genetics and Genome Biology , , Toronto, ON M5G 0A4 , Canada

2. University of Toronto 2 Department of Molecular Genetics , , Toronto, ON M5S 1A8 , Canada

3. the Hospital for Sick Children and University of Toronto 3 Division of Clinical Immunology and Allergy, Department of Pediatrics , , Toronto, ON M5G 1E8 , Canada

4. University of Toronto 4 Department of Physiology , , Toronto, ON M5S 1A8 , Canada

5. the Hospital for Sick Children 5 Program in Neuroscience and Mental Health , , Toronto, ON M5G 0A4 , Canada

6. the Hospital for Sick Children Research Institute 6 Program in Developmental and Stem Cell Biology , , Toronto, ON M5G 0A4 , Canada

7. the Hospital for Sick Children and University of Toronto 7 Division of Clinical and Metabolic Genetics, Department of Pediatrics , , Toronto, ON M5G 1X8 , Canada

8. Michigan State University 8 Department of Obstetrics, Gynecology and Reproductive Biology , , East Lansing, MI 48824 , USA

9. Institute for Quantitative Health Science and Engineering, Michigan State University 9 , East Lansing, MI 48824 , USA

Abstract

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 (‘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.

Funder

Reverse Rett Research Fund

Canadian Institutes of Health Research

Ontario Ministry of Health and Long-Term Care

Canadian Child Health Clinician Scientist Program

Hospital for Sick Children

Publisher

The Company of Biologists

Link

https://journals.biologists.com/dmm/article-pdf/doi/10.1242/dmm.050528/3515427/dmm050528.pdf

Reference74 articles.

1. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2;Amir;Nat. Genet.,1999

2. MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain;Balmer;Hum. Genet.,2002

3. Characterization of the FKBP·Rapamycin·FRB Ternary Complex;Banaszynski;J. Am. Chem. Soc.,2005

4. Infectious and Immunologic Phenotype of MECP2 Duplication Syndrome;Bauer;J. Clin. Immunol.,2015

5. Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus;Ben-Shachar;Hum. Mol. Genet.,2009