These mice carry a spontaneous mutation at the Irs1 locus characterized by hyperinsulinemia with only mild insulin resistance, a paucity of body fat, deficiencies in bone development and homeostasis, and hearing loss.Read More +
The small mutation causes hyperinsulinemia with only mild insulin resistance, a paucity of body fat, deficiencies in bone development and homeostasis, and hearing loss. Homozygotes can be distinguished by 2 weeks of age by their smaller body size and thin short tails, and adult homozygotes are visibly smaller with a tail that is 20% shorter than in wild-type controls. Hearing loss was shown through increased ABR threshold values when assessed between 8 and 12 weeks of age. The skeletal defects include shortened femurs with smaller growth plates, decreased cortical and trabecular thickness and abnormal trabecular number, with an increase in the number of osteoclasts and osteoblasts per bone perimeter but impaired osteoblast proliferation and differentiation in culture. This spontaneous point mutation is semidominant in some aspects of phenotype, unlike targeted mutations of this gene. Heterozygotes are statistically smaller than wild-type controls, but the severity of dwarfing is not readily apparent as it is with homozygotes. Heterozygotes also display an intermediate phenotype for serum insulin, femur length, reduction in femur growth plate size, bone mineral density, leanness, osteoblast function, cortical thickness, periosteal circumference, and mineral apposition rate. There is a variation by gender on the impact on bone structure such that female homozygotes have a decrease in trabecular number while males have an increase but those trabeculae are 34% thinner than normal, and the bone volume is more severely reduced in females than in males. An increase in osteoblasts and osteoclasts in the bone perimeter was found to reach statistical significance in female homozygotes but was less pronounced in male homozygotes. Additionally, in heterozygous females but not males fasting serum insulin like growth factor 1 is reduced to an intermediary level.
The Irs1sml mutation arose spontaneously on the C3.SW-H2b/SnJ strain (stock #000438) in the laboratory of Dr. Ed Birkenmeier at The Jackson Laboratory in approximately 1988. This mutation has been maintained via sibling intercrossing heterozygotes with homozygotes. In 2010 this strain reached generation F77.
|Gene Symbol and Name||Irs1, insulin receptor substrate 1|
|Strain of Origin||C3.SW-H2b/SnJ|
|Molecular Note||This spontaneous mutation has a deletion of one adenine in exon 1 at position 1559 which results in a frameshift leading to a premature stop codon predicted to yield only a 211 amino acid protein rather than the full-length 1233 amino acids. Western blot analysis using a C-terminus specific antibody failed to detect a protein product in liver extracts of homozygotes.|
|Allele Name||b variant|
|Allele Type||Not Applicable|
|Gene Symbol and Name||H2, histocompatibility-2, MHC|
|Strain of Origin||Not Applicable|
|General Note||The b variant has been observed in the following strains: C57BL/10, C57BL/10SnJ, BXSB/MpJ, C57BL/6J, C57L/J, LP/J, 129P3/J, 129P1/ReJ.|
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