B6.129-Gba1^tm1Clk/J

Stock number: 021329
Product name: FloxGBA
Research areas: Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

Exons 9-11 of Gba1 (glucosidase, beta, acid 1) are flanked by loxP sites in this conditional model, useful in studies of Gaucher disease.

Detailed description

Inherited deficiency of the lysosomal hydrolase, glucocerebrosidase (encoded by Gba1, glucosidase, beta, acid 1) underlies the autosomal recessive disorder, Gaucher disease. Excessive glucocerebroside storage may lead to the associated tissue dysfunctions. Affected individuals present with a spectrum of clinical symptoms ranging from hepatosplenomegaly, haematological abnormalities, and bone pain, to severe neurodegeneration and premature death. Homozygous knockouts of Gba1 in mice are perinatal lethal.

In this targeted allele, exons 9-11 are flanked by loxP sites enabling tissue-directed knockouts of the locus via Cre excision. Incomplete expression of Tie2Cre-recombinase (see Stock No. 004128) in cells of hematopoietic and endothelial origin results in deficiency of glucocerebrosidase in the liver, spleen, bone marrow, and peripheral white cells. Glucocerebroside storage in this model leads to progressive splenomegaly with Gaucher cell infiltration and modest storage in the liver by 26 weeks of age. No animals displayed obvious pathology in the bone marrow by 26 weeks of age, but small numbers of Gaucher cells could be found. No obvious haematological differences were seen in affected animals at 26 weeks of age.

LysMCre (see Stock No. 004781) and EIIaCre (see Stock No. 003724) conditional knockout mice fail to develop any notable pathology in the liver, spleen, and bone marrow by 26 weeks of age.

Development

A targeting vector was designed to place loxP sites on either side of Gba1 exons 9-11 and place an FRT-flanked neomycin cassette in reverse transcriptional orientation in intron 11. The targeting vector was injected into (129X1/SvJ x 129S1/Sv)F1- Kitl⁺-derived R1 embryonic stem (ES) cells. A Flpe-recombinase expression plasmid was introduced to targeted ES cells by electroporation to remove the neomycin resistance cassette. This strain was backcrossed to C57BL/6J for 11 generations by the donating laboratory.

Allele

Symbol: Gba1^tm1Clk
Name: targeted mutation 1, Lorne A Clarke
MGI accession ID: MGI:3698018
Generation method: Targeted
Attributes: Conditional ready (e.g. floxed); No functional change
Marker symbol: Gba1
Marker name: glucosylceramidase beta 1
Chromosome: 3
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: A targeting vector was designed to flank exons 9-11 with loxP sites. An frt-flanked neo was inserted as well as exons 8-4 of metaxin 1 in reverse orientation. The neo was removed by transient expression of FLP recombinase.