title: CRISPR-Cas9-Mediated Modification of the NOD Mouse Genome With Ptpn22R619W Mutation Increases Autoimmune Diabetes.
abstract: An allelic variant of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), PTPN22(R620W), is strongly associated with type 1 diabetes (T1D) in humans and increases the risk of T1D by two- to fourfold. The NOD mouse is a spontaneous T1D model that shares with humans many genetic pathways contributing to T1D. We hypothesized that the introduction of the murine orthologous Ptpn22(R619W) mutation to the NOD genome would enhance the spontaneous development of T1D. We microinjected CRISPR-Cas9 and a homology-directed repair template into NOD single-cell zygotes to introduce the Ptpn22(R619W) mutation to its endogenous locus. The resulting Ptpn22(R619W) mice showed increased insulin autoantibodies and earlier onset and higher penetrance of T1D. This is the first report demonstrating enhanced T1D in a mouse modeling human PTPN22(R620W) and the utility of CRISPR-Cas9 for direct genetic alternation of NOD mice.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Stephane
authors.initials: S
authors.lastname: Pelletier
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gingras
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rigaud
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Maine
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Marquardt
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.
authors.forename: Yang D
authors.initials: YD
authors.lastname: Dai
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Sauer
authors.affiliation: Murine Genetics Core, The Scripps Research Institute, La Jolla, CA.
authors.forename: Alberto R
authors.initials: AR
authors.lastname: Rodriguez
authors.affiliation: Murine Genetics Core, The Scripps Research Institute, La Jolla, CA.
authors.forename: Greg
authors.initials: G
authors.lastname: Martin
authors.affiliation: Murine Genetics Core, The Scripps Research Institute, La Jolla, CA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kupriyanov
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA lsherman@scripps.edu.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Sherman
mesh_terms: D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D064113:CRISPR-Cas Systems / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D016678:Genome / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse