NOD.Cg-Idua^tm1Clk Prkdc^scid Il2rg^tm1Wjl/J

Stock number: 035007
Product name: NSG MPS I
Strain synonyms: NSG MPS I
Research areas: Cancer Research, Developmental Biology Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Metabolism Research, Mouse/Human Gene Homologs, Neurobiology Research, Research Tools, Virology Research

Description

NSG MPS I animals combine the features of NSG™ mice (including the C5 complement deficiency, B and T cell deficiency, and NK cell deficiency) with a targeted knock-out of the mouse Idua (iduronidase, alpha-L) gene contributing a mucopolysaccharidosis type I (MPS I) lysosomal storage disorder phenotype. This severely immunodeficient strain provides an effective model for human cell transplantation/engraftment, and studies of MPS I.

Detailed description

NSG MPS I animals combine the features of NSG™ mice (including the C5 complement deficiency of the NOD genetic background, B and T cell deficiency of the scid mutation, and NK cell deficiency of Il2rg (“gamma”) knock-out allele) with a targeted knock-out of the mouse Idua (iduronidase, alpha-L) gene contributing a mucopolysaccharidosis type I (MPS I; Hurler syndrome) lysosomal storage disorder phenotype.

The development of this strain was inspired by a publication by Dr. Philip Schwartz's group (CHOC Research Institute; PMID 26052536). These mice were generated through crosses of NOD.Cg-Prkdc^scid Idua^tm1Clk/J (Stock No. 004083) mice with NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (Stock No. 005557) animals at The Jackson Laboratory. The phenotypic information provided for this strain is largely based on the Schwartz lab findings.

Female mice that are homozygous for all 3 mutations, and males that are homozygous for the Idua and Prkdc^scid mutations and hemizygous for the X-linked Il2rg mutation appear normal at birth, but begin to develop MPS I-like phenotypes by 3-15 weeks of age. NSG MPS 1 mice are initially distinguishable by a rough coat appearance. Craniofacial abnormalities (a broadened head, less pointed nose, smaller ears, and deep-set eyes) are also characteristic. As the animals age, they develop kyphosis, other skeletal abnormalities, and an abnormal gait as they become less ambulatory. Impaired performance in behavioral tests is observed as significant inflammation and prominent gliosis are found in the brain.

Levels of glucosaminoglycan (GAG) expression are elevated in multiple tissue types including the heart, liver, brain, kidney, lung, and spleen. Urinary excretion of GAG is consistently elevated. The affected mice live for more than a year during which they do not develop thymic lymphomas.

Human CD34+ hematopoietic stem cells (HSCs) have been demonstrated to readily engraft in NSG MPS 1 mice, producing identifiable T- and B- cell subpopulations. Human neuronal stem cells (NSCs) effectively engraft in the brain post-intracerebroventricular injection and remain detectable for at least 1 year without immunosuppression.

For comparison, Stock No. 035868 and Stock No. 035007 (this strain) carry differing Idua knock-out mutations on an NSG™ background, but develop similar phenotypes. The Idua knock-out allele found in this strain (Idua^tm1Clk) was created by Lorne Clark's group at the University of British Columbia and has been widely used in therapeutic MPS1 therapy studies, thus has been well-characterized. The CRISPR-generated W392X mutation in Stock No. 035868 (Idua^em1Osp) is analogous to a known disruptive W402X human gene mutation. Legal constraints prohibit the distribution of 035868 to for-profit entities. Stock No. 035007 is available to both non-profit and for-profit groups. Please see the legal section for further details. (March, 2022)

Maintaining these severely immunocompromised mice under specific pathogen-free conditions is recommended to promote their overall health. Please see our NSG housing and breeding information for additional details.

Development

NSG MPS I mice were generated through crosses of NOD.Cg-Prkdc^scidIdua^tm1Clk/J (Stock No. 004083) with NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (Stock No. 005557) at The Jackson Laboratory.

In brief:
Prkdc^scid: This spontaneous mutation, incorporating a T-to-A transversion point mutation in codon 4046, occurred in a colony of BALB/c-Igh^b (C.B-17) mice maintained at the Institute for Cancer Research in Philadelphia, PA. The mutation creates a premature stop codon.

Il2rg^tm1Wjl: A targeting vector containing a neomycin resistance cassette was used to disrupt part of exon 3 and all of exons 4 through 8 of the Il2rg gene.

Idua^tm1Clk: A targeting vector containing a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt exon 5 of the Idua gene.

Maintenance of this strain will involve NOD.Cg-Prkdc^scidIdua^tm1Clk/J (Stock No. 004083), NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (Stock No. 005557), and/or NOD/ShiLtJ (Stock No. 001976).

Allele

Symbol: Prkdc^scid
Name: severe combined immunodeficiency
MGI accession ID: MGI:1857113
Generation method: Spontaneous
Synonyms: scid
Marker symbol: Prkdc
Marker name: protein kinase, DNA activated, catalytic polypeptide
Marker synonyms: DNAPDcs; DNAPK; DNA-PK; DNAPKc; DNA-PKC; DNA-PKcs; DNPK1; DOXNPH; dxnph; HYRC; HYRC1; IMD26; p350; S473K; slip; XRCC7
Chromosome: 16
Strain of origin: C.BKa-Igh^b/Icr
Site of expression: T and B lymphocytes.
Molecular note: A T-to-A transversion point mutation at a position corresponding to codon 4046 (codon 4095 in transcript ENSMUST00000023352.8) created a premature stop codon (p.Y4046*).

Allele

Symbol: Il2rg^tm1Wjl
Name: targeted mutation 1, Warren J Leonard
MGI accession ID: MGI:1857455
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: [KO]gammac; CD132^-; gammac^-; gc^-; Il2rg^tm1Wjll; IL2Rgamma^null
Marker symbol: Il2rg
Marker name: interleukin 2 receptor, gamma chain
Marker synonyms: [g]c; Ab2-183; Cd132; CIDX; common cytokine receptor gamma chain; common gamma chain; gamma C receptor; gamma(c); gammaC; gc; IL-2RG; IMD4; P64; SCIDX; SCIDX1
Chromosome: X
Strain of origin: 129S4/SvJae
Site of expression: Primarily lymphoid cells.
Molecular note: A neomycin resistance cassette replaced part of exon 3 and all of exons 4 - 8 of the gene, resulting in the loss of most of the extracellular domain and all of the transmembrane and cytoplasmic domains of the protein.

Allele

Symbol: Idua^tm1Clk
Name: targeted mutation 1, Lorne A Clarke
MGI accession ID: MGI:2176236
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Idua
Marker name: iduronidase, alpha-L
Marker synonyms: IDA; MPS1; MPSI
Chromosome: 5
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: A neomycin selection cassette was inserted into exon 6. RT-PCR analysis on RNA derived from liver and kidney of homozygous mice demonstrated that no detectable transcript was produced from this allele. Enzymatic activity assays on homogenates of liver, kidney, brain and tail clippings of homozygous mice confirmed that no functional protein was expressed from this allele.