Mice homozygous for the yellow spontaneous mutation (Ay) die before implantation or shortly thereafter. Heterozygotes usually become obese and infertile within a few months after birth. Heterozygotes are more susceptible to several kinds of tumors than are normal mice. Further, spleen cells from heterozygotes cause a significantly lower graft vs. host reaction. Mice of the KK strain develop diabetes of polygenic origin, and KK.Cg-Ay/J heterozygotes develop hyperglycemia, hyperinsulinemia, glucose intolerance and obesity by eight weeks of age. Pancreatic islets are hypertrophied and the β-cells are degranulated. Both the fat and lean tissue mass are increased compared to non-obese mice, with fat accounting for 30-35% of total body weight.
It has been reported that the KK strain is hemolytic complement deficient (Hc0), however, our strains have not been tested to confirm this allele. (Cinader B, et al.,2004, J Exp Med,120:897)
Ay and other mutations at the a locus conferring a completely yellow coat color are dominant to all a alleles that produce a darker coat. Hair pigment of Ay heterozygotes is yellow, but eyes are black. Heterozygotes usually become obese and infertile within a few months after birth. Increased adipose tissue mass is due to fat cell hypertrophy, and it has been hypothesized that the obesity results from the observed reduction in hypothalamic norepinephrine and dopamine. Heterozygotes are more susceptible to several kinds of tumors than are normal mice, possibly due, at least in part, to a general increase in cell proliferation that also manifests as a slight increase in lean body mass and skeletal length. Further spleen cells from heterozygotes cause a significantly lower graft vs. host reaction. Mice homozygous for the yellow spontaneous mutation (Ay) die before implantation, or shortly thereafter. The time of death and type of abnormality is, in part, determined by the genetic background on which the mutation is placed. Mice of the KK strain develop diabetes of polygenic origin, and mice of other strains heterozygous for Ay become obese and mildly diabetic. KK.Cg-Ay/J heterozygotes develop hyperglycemia, hyperinsulinemia, glucose intolerance and obesity by eight weeks of age. Studies using isolated adipocytes indicate that tissue responsiveness to insulin is decreased. Histo- and immunocytochemical studies show that the pancreatic islets are hypertrophied and the β-cells are degranulated. These findings suggest that the principal cause of diabetes in these mice is insulin resistance. Body composition analysis shows that both the fat and lean tissue mass are increased compared to non-obese mice, with fat accounting for 30-35% of total body weight. The pleiotropic mutant phenotype of Ay/a mice is attributed to ectopic expression of the agouti protein, while the early embryonic lethality of the Ay mutation in the homozygous state is assumed to result from lack of expression of the Raly gene product (Bultman et al. 1992, Miller et al. 1993, Duhl et al. 1994, Michaud et al. 1993, 1994). That ectopic expression of the agouti protein is probably responsible for the non-lethal aspects of this mutation has been demonstrated by transgenic expression of the protein from a ubiquitous promoter (Klebig et al. 1995, Perry et al. 1995).
For further information, see Mouse Genome Informatics entries for a and for Raly and Michael F.W. Festing's description of KK.
The Ay mutation was introduced onto the KK strain background by Dr. Nishimura in Japan. The Upjohn (Upj) colony of KK-Ay mice was initiated from mice acquired from Takeda Chemical Industries (Osaka, Japan) by Dr. George Gerritsen in 1983, at which time they had been inbred for 100 generations. The original KK-Ay strain was developed following initial crosses of Ay/a mice with mice of one of the inbred KK strains established from native Japanese mice (Kondo et al. 1957). As the diabetic characteristics of KK mice are generally considered to be of polygenic origin (Coleman 1982, Reddi and Camerini-Davalos 1988) and as Kondo established multiple sublines of KK mice, it is uncertain how closely related KK.Cg-Ay/J is to other KK strains. The Jackson Laboratory distributes the KK/HlJ (Stock No. 002106) obtained from Dr. Leiselotte Herberg at the Diabetes Research Institute in Dusseldorf, Germany. Additional backgrounds available: C57BL/6J-Ay.
|Allele Name||agouti yellow|
|Allele Synonym(s)||A(y); Ay|
|Gene Symbol and Name||a, nonagouti|
|Gene Synonym(s)||AGSW; AGTI; AGTIL; ASP; As; As; SHEP9; agouti; agouti signal protein; agouti suppressor|
|Strain of Origin||old mutant of the mouse fancy|
|General Note||Phenotypic Similarity to Human Syndrome: Metabolic Syndrome in mice homozygous for Apoetm1Unc and heterozygous for Ay and a (J:177084) |
|Molecular Note||The Ay mutation appears to be a DNA structural alteration that disrupts a gene, hnRNP associated with lethal yellow (Raly), 5' to the agouti locus and places the agouti locus under the control of the Raly promotor. A report of recombination between Ay and the a and ax alleles suggests that Ay was a pseudoallele of the a locus on the proximal side. However, cloning of the agouti locus and molecular analysis of a showed that the coding region of the three allelesis identical.|
Coat color is used to determine genotypes of our KK.Cg-Ay/J colony. Black (a/a homozygous) females are bred to yellow (Ay/a) males. All offspring with the Ay/a mutation and phenotype are yellow, the wild-type mice are black.
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