B6.Cg-Dock7^m Lepr^db/+ +/J

Stock number: 000699
Product name: B6-diabetes
Research areas: Dermatology Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Metabolism Research, Mouse/Human Gene Homologs, Reproductive Biology Research

Description

These mice carry a spontaneous mutation at the Lepr locus on a C57BL/6J background and are characterized by compensatory hyperplasia of the islet B-cells and hyperinsulinemia. Wound healing is delayed, and metabolic efficiency is increased. The strain carries the misty mutation (Dock7^m) to aid in early identification of homozygotes.

Detailed description

Mice homozygous for the diabetes spontaneous mutation (Lepr^db) become identifiably obese around 3 to 4 weeks of age. Elevations of plasma insulin begin at 10 to 14 days and of blood sugar at 4 to 8 weeks. Affected mice are polyphagic, polydipsic, and polyuric. The course of the disease is markedly influenced by genetic background. On the C57BL/6 background there is compensatory hyperplasia of the islet B-cells, and continued hyperinsulinemia throughout an 18- to 20-month life span. Wound healing is delayed, and metabolic efficiency is increased. Although normal in body weight, blood glucose, and plasma insulin, heterozygotes (Lepr^db/+) 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 Lepr^db may cause a defect in the hypothalamus. Steroid sulfotransferase enzymes, aberrantly expressed in diabetic mice, interact with the Lepr^db mutation as modifiers of gender differences in obesity-induced diabetes susceptibility. Because Lepr^db homozygotes are functionally sterile, the coat color marker misty (Dock7^m) has been incorporated into stocks for maintenance of the diabetes mutation. The coupling double heterozygote, (Dock7^m Lepr^db/+ +, this strain) allows identification of homozygotes before the phenotype becomes severe.

The recessive misty mutation causes a mild dilution of coat color. On certain backgrounds, a white tail tip often accompanied by a belly spot is also present. Melanocytes from homozygous misty mice (Dock7^m/Dock7^m) have a highly dendritic shape, show deficient proliferation in culture and have much more melanin content. Fewer melanoblasts are found in primary cultures from Dock7^m/Dock7^m mice than from wildtype controls. Between two and five weeks of age, Dock7^m/Dock7^m 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, bleed time is increased and platelet AD levels are reduced in Dock7^m/Dock7^m homozygotes. (Woolley, 1941 and 1945; Truett et al. 1998; Sviderskaya et al. 1998.)

Development

The strain was cryopreserved in 1990 at generation N6F36.

Allele

Symbol: Dock7^m
Name: misty
MGI accession ID: MGI:1856946
Generation method: Spontaneous
Marker symbol: Dock7
Marker name: dedicator of cytokinesis 7
Chromosome: 4
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 (Dock7^mnlt), 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

Symbol: Lepr^db
Name: diabetes
MGI accession ID: MGI:1856009
Generation method: Spontaneous
Marker symbol: Lepr
Marker name: leptin receptor
Chromosome: 4
Strain of origin: C57BLKS/J
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.
General note:

Phenotypic Similarity to Human Syndrome: Gestational Diabetes J:219658