This strain is used to model phases I to III of diabetes type II and obesity. Mice homozygous for the diabetes spontaneous mutation (Leprdb) manifest morbid obesity, chronic hyperglycemia, pancreatic beta cell atrophy and become hypoinsulinemic. Obesity starts at 3 to 4 weeks of age. Elevated plasma insulin begins at 10 to 14 days and elevated blood sugar at 4 to 8 weeks. Homozygous mice are polyphagic, polydipsic, and polyuric. The severity of disease on BKS background leads to uncontrolled rise in blood sugar, severe depletion of insulin-producing beta-cells of the pancreatic islets, peripheral neuropathy, myocardial disease and death by 10 months of age. Exogenous insulin fails to control blood glucose levels and gluconeogenic enzyme activity increases. Wound healing is delayed, and metabolic efficiency is increased.Read More +
This strain is maintained with Dock7m and Leprdb in repulsion. Although these genes are tightly linked, there is a small possibility of recombination. The heterozygotes we distribute are presumed to be non-recombinant, but are untested.
Mice homozygous for the diabetes spontaneous mutation (Leprdb) become identifiably obese around three to four weeks of age. Elevations of plasma insulin begin at 10 to 14 days of age and of blood sugar at four to eight weeks. Homozygous mutant mice are polyphagic, polydipsic, and polyuric. The course of the disease is markedly influenced by genetic background. A number of features are observed on the C57BLKS background, including an uncontrolled rise in blood sugar, severe depletion of the insulin-producing beta-cells of the pancreatic islets, and death by 10 months of age. Exogenous insulin fails to control blood glucose levels and gluconeogenic enzyme activity increases. Peripheral neuropathy and myocardial disease are seen in C57BLKS-Leprdb homozygotes. Wound healing is delayed, and metabolic efficiency is increased. Female homozygotes exhibit decreased uterine and ovarian weights, decreased ovarian hormone production and hypercytolipidemia in follicular granulosa and endometrial epithelial tissue layers (Garris et al., 2004, Garris et al., 2004).
Although normal in body weight, blood glucose, and plasma insulin, heterozygotes (Leprdb/+) also have increased metabolic efficiency and can survive a prolonged fast longer than controls. Experiments involving destruction of the ventromedial nucleus of the hypothalamus suggest that Leprdb may cause a defect in the hypothalamus. Steroid sulfotransferase enzymes, aberrantly expressed in diabetic mice, interact with the Leprdb mutation as modifiers of gender differences in obesity-induced diabetes susceptibility. Because of the sterility of Leprdb homozygotes, the misty (Dock7m) mutation has been incorporated into stocks for maintenance of the diabetes mutation. The repulsion double heterozygote (Dock7m +/+ Leprdb) facilitates identification of heterozygotes for breeding, while the coupling double heterozygote, (Dock7m Leprdb/+ +) allows identification of homozygotes before the phenotype becomes severe.
The recessive misty mutation causes a mild dilution of coat color and on certain backgrounds a white tail tip often accompanied by a belly spot. Melanocytes from Dock7m/Dock7m mice have a highly dendritic shape, show deficient proliferation in culture and have much more melanin content. Fewer melanoblasts are found in primary cultures from Dock7m/Dock7m mice than from wildtype controls. Between two and five weeks of age, Dock7m/Dock7m mice are smaller than controls. At 35 days of age they are shorter, weigh 15% less on average, and have less inguinal adipose mass than controls. Misty homozygotes completely lack brown fat. Although platelet count, seratonin content and ATP content are normal, Dock7m/Dock7m homozygotes have an increased bleed time and reduced platelet ADP levels.(Woolley 1941 and 1945; Truett et al. 1998; Sviderskaya et al. 1998.)
|Gene Symbol and Name||Dock7, dedicator of cytokinesis 7|
|Strain of Origin||DBA/J|
|Molecular Note||Crosses between mice homozygous for misty and for moonlight, which mapped to overlapping critical regions on Chr 4, demonstrated failure of the two mutations to complement one another. Once moonlight had been identified as a mutation of Dock7 (Dock7mnlt), sequence analysis of this gene from misty mice revealed a retrotransposon LTR insertion following nucleotide 2045 (numbering from the A of the transcription initiation codon) that interrupts exon 18 and shifts the reading frame after codon 682 so that ten incorrect amino acids are incorporated into the protein before its premature termination.|
|Allele Synonym(s)||db; db/db; Lepdb; Lepr-; Leprdb-1J; leprdb|
|Gene Symbol and Name||Lepr, leptin receptor|
|Strain of Origin||C57BLKS/J|
|General Note|| |
Phenotypic Similarity to Human Syndrome: Gestational Diabetes J:219658
|Molecular Note||An intronic G-to-T transversion in this allele created a donor splice site that causes abnormal splicing and the inclusion of 106 nt of intronic sequence in the transcript, leading to premature termination of the long cellular domain of the Ob-Rb splice form and loss of its signal transducing function.|
Since both males and females homozygous for Leprdb are sterile, the closely linked coat color mutation, m, has been incorporated into stocks for maintenance of the db mutation. Breeding is performed by mating repulsion double heterozygotes, Dock7m +/+ Leprdb, which presumably yield 1/4 diabetics (black, obese at weaning) for studies , 1/2 wild-type repulsion double heterozygotes (black, lean) for futher breeding, and 1/4 misty mice (grey, lean) that can be discarded. The risk of recombination between the Dock7m and Leprdb loci is only about 2%, recognizable in pups as young as 3 days old by absence of pigment in paws and tip of tail. Dietary restrictions can prolong life and carbohydrate-free, protein-enriched defined diets can diminish the significantly the severity of the disease.
Wean-aged mice may show signs of barbering that include whisker picking. Affected mice typically regrow whiskers within two weeks after weaning.
When using the BKS.Cg-Dock7m +/+ Leprdb/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #000642 in your Materials and Methods section.
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