NOD.Cg-Prkdc^scid Gla^tm1Kul/MedinJ

Stock number: 039414
Product name: NOD Scid Fabry
Strain synonyms: NOD Scid α-Gal A KO
Research areas: Developmental Biology Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Metabolism Research, Research Tools, Virology Research

Description

NOD scid Fabry knock-out mice harbor an α-Gal A^- knock-out allele (Stock No. 003535) on a NOD scid background (Stock No. 001303). This severely immunodeficient strain provides an effective model for human cell transplantation/engraftment when studying the lysosomal storage disorder, Fabry disease.

Of note, the α-Gal A^- knock-out allele is available on a mixed B6;129 genetic background (Stock No. 003535) and on a C57BL/6J congenic background (Stock No. 036174).

Detailed description

NOD Scid Fabry (NSF) mice contain a neo cassette replacing exon 3 and intron 3 of the galactosidase, alpha (Gla) gene, abolishing gene expression on a congenic NOD scid (Stock No. 001303) background. GLA is an X-linked gene that encodes a ubiquitously expressed lysosomal hydrolase. Mutations in GLA have been associated with the development of Fabry disease, a lysosomal storage disorder caused by a buildup of a fat called globotriaosylceramide. Fabry disease is characterized by pain, particularly in the hands and feet (acroparesthesias), angiokeratomas, hypohidrosis, corneal opacity, gastrointestinal issues, tinnitus, and hearing loss. Fabry disease can also lead to life-threatening complications such as progressive kidney damage, heart attack, and stroke. Mutations have also been associated with Alzheimer's disease, epilepsy, depression, eating disorders, and impaired cognitive function.

Females homozygous for both alleles and males that are homozygous for Prkdc^scid and hemizygous for Gla^tm1Kul are viable and fertile. GLA activity in these NSF mice are comparable to the enzyme activity in the mixed genetic background mouse model (Stock No. 003535) across multiple tissues. The donating laboratory notes that the NSF mice have a survival of 9 months up to 1 year of age, due to complications with immune deficiency. Though not confirmed in these NSF mice, hemizygous males on a mixed genetic background display abnormal kidney and liver morphology, both with accumulations of globotriaosylceramide. Hemizygous males, on a mixed genetic background, also exhibit mild cardiomyopathy and abnormal cardiovascular physiology; it is not known if these NSF mice also display cardiac abnormalities. These NSF mice may be useful for evaluating human cell-based therapies for Fabry disease.

Of note, the α-Gal A^- knock-out allele is available on a mixed B6;129 genetic background (Stock No. 003535) and on a C57BL/6J congenic background (Stock No. 036174).

Development

The NOD scid Fabry (NSF) mouse model was generated by backcrossing an α-Gal A^- allele on a mixed genetic background (JAX Stock No. 003535) on to a NOD scid background (JAX Stock No. 001303).

The α-Gal A^- targeting vector was designed to replace exon 3 and intron 3 of the galactosidase, alpha (Gla) gene with a neomycin resistance (neo) cassette. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric males were bred to C57BL/6 females. These mice were maintained on a mixed genetic background prior to sending males to The Jackson Laboratory Repository.

The Prkdc^scid mutant allele occurred spontaneously in a colony of BALB/c-Igh^b (C.B-17) mice maintained at the Institute for Cancer Research in Philadelphia, PA. The Prkdc^scid mutation was backcrossed onto the NOD/ShiLtSz background as follows: an NOD/ShiLtSz female was bred to a C.B-17-Prkdc^scid male; male Prkdc^scid/+ offspring of the F1/N1 and subsequent generations were mated to NOD/ShiLt females for a total of 10 crosses to NOD/ShiLtSz; at generation N10, Prkdc^scid was made homozygous by brother-sister inbreeding.

Dr. Jeffrey Medin (Medical College of Wisconsin) acquired some α-Gal A^- mice, on mixed genetic background (JAX Stock No. 003535) and backcrossed these to NOD scid (JAX Stock No. 001303) for at least 11 generations before sending mice back to The Jackson Laboratory. The resulting NOD scid congenic strain is called NOD.Cg-Prkdc^scid Gla^tm1Kul/MedinJ, Stock No. 039414. To establish our live colony, an aliquot of frozen sperm was used to fertilize NOD.Cg-Prkdc^scid/J (Stock No. 001303) oocytes.

Allele

Symbol: Gla^tm1Kul
Name: targeted mutation 1, Ashok B Kulkarni
MGI accession ID: MGI:1861794
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: alpha-Gal A -/0; alpha-galA^-; Gla-
Marker symbol: Gla
Marker name: galactosidase, alpha
Marker synonyms: Ags; GALA
Chromosome: X
Strain of origin: 129S4/SvJae
Molecular note: A 1kb genomic fragment containing part of exon 3 and intron 3 was replaced by a neomycin resistance cassette.

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*).