Mice homozygous for this targeted mutation of the bradykinin receptor, beta 2 (Bdkrb2) gene and heterozygous for the Akita spontaneous mutation of the insulin 2 (Ins2) gene (Ins2Akita) are viable and fertile. They are extremely diabetic, underweight, hyperphagic, polyuric, and have severe kidney, skeletal, and testicular defects. essentially no subcutaneous fat, and a significantly reduced lifespan. This strain may be used to research the kallikrein-kinin system, specifically the role of bradykinin B2 receptor in diabetes, oxidative stress, mitochondrial DNA damage, apoptosis, kidney morphology and function, and other senescence-associated phenotypes.
Dr. Masao Kakoki, University of North Carolina at Chapel H
Mice homozygous for the targeted mutation and heterozygous for the Ins2Akita spontaneous mutation are viable and fertile. Similar to mice only heterozygous for the Ins2Akita mutation, the double mutant mice are severely diabetic: their body weights are 70% of wildtype, they consume over 3-fold the normal amount of food, and their urinary output is approximately 20-fold more than that of wildtype mice. Double mutant mice have markedly enlarged kidneys. Urinary albumin excretion in double mutants is almost 4-fold that of either single mutant, and double mutants experience more severe nephropathy than mice that are heterozygous for the Akita mutation alone. Megsin and nephrin expression is markedly increased in double mutant mice when compared to wildtype or to mice with either single mutation alone. By 12 months of age, double mutant mice experience hair loss due to a reduction in hair follicle numbers and thinning of the dermis. Double mutants have essentially no subcutaneous fat, severe kyphosis, reduced bone density, osteoporosis, testicular atrophy, lipofuscin accumulation in the renal proximal tubule and testicular Leydig cells, increased apoptosis in the testicular seminiferous tubules and intestinal villi, and a significantly reduced lifespan.
This model is useful for studying the kallikrein-kinin system, specifically the role of bradykinin B2 receptor in diabetes, oxidative stress, mitochondrial DNA damage, apoptosis, morphological and functional kidney changes, and other senescence-associated phenotypes.
Dr. Oliver Smithies laboratory backcrossed Stock No. 002641 B6;129S7-Bdkrb2tm1Jfh/J mice to C57BL/6J (Stock No. 000664) for an additional 6 generations prior to mating to Stock No. 003548 C57BL/6-Ins2Akita/J. In 2007, The Jackson Laboratory received C57BL/6 congenic males homozygous for the Bdkrb2tm1Jfh mutation at N9F? and mated them to heterozygous females from Stock No. 003548 C57BL/6-Ins2Akita/J. The strain has been maintained subsequently by brother x sister matings.
Genetic quality control completed at The Jackson Laboratory indicates that there is 129 genetic contamination on chromosomes 3, 4, 6, 11, 15 and 17 (006860 SNP's marker data)
|Allele Name||targeted mutation 1, J Fred Hess|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||B2-; B2-KO; B2R-; BdkrB2; Bk B2R-; Bk2r-; rB2 -|
|Gene Symbol and Name||Bdkrb2, bradykinin receptor, beta 2|
|Gene Synonym(s)||B(2); B2; B2BKR; B2BRA; B2R; BK-2; BK2; BK2R; BKR2; BRB2; kinin B2|
|Strain of Origin||129S7/SvEvBrd-Hprt |
|Molecular Note||A neomycin selection cassette replaced the entire coding sequences of the gene. Binding assays on membranes prepared from ileum tissue of homozygous mice confirmed that no functional protein is produced from this allele.|
|Mutations Made By|| |
Dr. J. Hess, Merck Research Laboratories
|Allele Synonym(s)||Akita; AkitaIns2; Ins2C96Y; Ins2Mody; Mody; Mody4|
|Gene Symbol and Name||Ins2, insulin II|
|Gene Synonym(s)||AA986540; CP-II; IDDM; IDDM1; IDDM2; ILPR; IRDN; Ins-2; Ins-2; InsII; MODY10; Mody; Mody; Mody4; Mody4; expressed sequence AA986540; maturity onset diabetes of the young; maturity onset diabetes of the young 4|
|Strain of Origin||C57BL/6NSlc|
|General Note||Phenotypic Similarity to Human Syndrome: Type 1 Diabetic Macrovascular Disease (J:174983)|
|Molecular Note||In the mutant allele a transition from G to A at nucleotide 1907 disrupted an Fnu4HI site in exon 3. This mutation changed the seventh amino acid in the A chain of mature insulin, Cys96 (TGC), to Tyr (TAC). The authors predict that the transition would disrupt a disulfide bond between the A and the B chains and would likely induce a major conformational change in insulin 2 molecules. RT-PCR studies suggest that both normal and mutant Ins2 alleles are transcribed similarly in pancreatic islets of heterozygous mice, although immunofluorescence and immunoblot analyses of heterozygous islets detected reduced levels of insulin and proinsulin.|
|Please inquire about possible genotypes.|
The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided,
their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of
each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders
are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in
order to provide the minimum number of animals, animals will ship within 25 weeks.
The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.
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