This congenic NOD strain contains a neomycin cassette that disrupts exon 4 of cathepsin B (Ctsbtm1Jde). NOD Ctsb deficient mice exhibit modestly delayed diabetes onset. This model provides a tool for detailed studies to identify the molecular pathways of major lysosomal cysteine proteases, specifically cathepsin B, in immune modulation.
Dr. Renee C LeBoeuf, Universtiy of Washington
Mice homozygous for the Ctsb targeted mutation are viable, fertile, normal in size, and do not display any gross physical or behavioral abnormalities. Northern blot analysis of kidney total RNA indicates a lack of transcript in homozygous mutant mice. An absence of Ctsb protein in homozygous mutant mice was determined by Western blot analysis of kidney lysosomal protein extracts. The proteolytic activity of the endogenous protein was found to be absent using an assay involving liver lysosomal extracts, obtained from homozygous mutant mice, and a fluorogenic substrate (Halangk et al. 2000).
The donating investigator indicates that the diabetes incidence in homozygous mutant NOD mice is significantly reduced (28%) compared to wildtype NOD (69%), while heterozygous mice are modestly protected from diabetes (50%) at six months of age. Histological analysis of the pancreas from non-diabetic homozygous mice indicate that insulitis is present but at much lower levels than in diabetic homozygous mice. Heterozygous mice had severe insulitis, indicating that the loss of one Ctsb allele is associated with delayed diabetes onset. Thyroiditis and sialadentis scores of mutant and NOD mice are equivalent. Data collected indicates that the loss of Cathepsin B delays but does not halt diabetes onset.
This model provides a tool for detailed studies focused on the identification of the molecular pathways of major lysosomal cysteine proteases, specifically cathepsin B, in immune modulation.
The Cathepsin B gene, located on Chromosome 14, 63.7Mb, was disrupted via homologous recombination in 129P2/OlaHsd-derived, E14.1 ES cells. A neomycin cassette was inserted into a BglII site in exon 4; which introduced a premature stop codon into the open reading frame of the Ctsb gene. The resulting ES cell clone was injected into C57BL/6 blastocysts. The chimeric founder's offspring were bred to C57BL/6J prior to 10 generations of crossing to NOD and intercrossing. Marker assisted analysis indicate 19 known Idd loci which are of NOD origin. In 2008, the T1DR received this strain at generation N11F2.
|Allele Name||targeted mutation 1, Jan Deussing|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||CTSB-; Cat B-; CathB-; Ctsb-|
|Gene Symbol and Name||Ctsb, cathepsin B|
|Gene Synonym(s)||APPS; CB; CPSB|
|Strain of Origin||129P2/OlaHsd|
|General Note||in combination with Ctsltm1Cptr, double homozygous mutant have some similarities but distinct phenotypic characteristics compared to the human syndrome: neuronal ceroid lipofuscinoses (NLCs)|
|Molecular Note||A neomycin selection cassette was inserted into a BglII site in exon 4. Northern blot analysis of total RNA showed a lack of transcript in homozygous mutant mice. An absence of protein in homozygous mutant mice was determined by Western blot analysis of kidney lysosomal protein extracts. The proteolytic activity of the endogenous protein was found to be absent using an assay involving liver lysosomal extracts obtained from of homozygous mutant mice and a fluorogenic substrate.|
|Mutations Made By|| |
Dr Jan Deussing, Max-Planck-Institute of Psychiatrie
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