Mice homozygous for the tubby spontaneous mutation experience maturity-onset obesity. Homozygous mutant mice are recognizable by increased body weight at 3 to 4 months in males and at 4 to 6 months in females. Both sexes are fertile. The increased weight is composed of excess adipose tissue. Blood glucose is normal, but plasma insulin is increased prior to obvious signs of obesity and may rise to 20 times normal by 6 months. Despite elevated plasma total cholesterol, triglycerides, and high-density lipoprotein cholesterol, homozygous mutant mice do not exhibit atherosclerotic fatty streak blood vessel lesions. Tubby mutant mice also exhibit retinal degeneration, initially believed due to the presence of another mutation which was called rd5, but since demonstrated to be a pleiotropic effect of the Tubtub mutation (Ohlemiller et al., 1997); the retinal phenotype is moderated by a QTL on Chromosome 11 (Ikeda et al., 2002). Tubby homozygotes additionally exhibit progressive hearing loss. The hearing loss is due to apoptotic degeneration of the organ of Corti and loss of afferent neurons. Quantitative trait locus (QTL) analysis identified a region on Chromosome 2 (designated modifier of tubby hearing 1, moth1) whose wild-type allele protects tubby mice from hearing loss (Ikeda et al., 1999); the gene has been identified as Mtap1a, encoding a microtubule-associated protein (Ikeda et al., 2002). A locus suggestively associated with protection from retinal degeneration maps to the same region of Chromosome 2 (Ikeda et al., 2002). Mice homozygous for a targeted null mutation in the tubby gene (not currently available from The Jackson Laboratory) exhibit a phenotype identical to that conferred by the spontaneous tubby mutation (Stubdal, et al., 2000).
