A candidate gene for the mouse mutation tubby.

A mutation in the tub gene causes maturity-onset obesity, insulin resistance, and sensory deficits. In contrast to the rapid juvenile-onset weight gain seen in diabetes (db) and obese (ob) mice, obesity in tubby mice develops gradually, and strongly resembles the late-onset obesity seen in the human population. Excessive deposition of adipose tissue eventually leads to a twofold increase of body weight. Tubby mice also suffer retinal degeneration and neurosensory hearing loss. The tripartite character of the tubby phenotype shows striking similarity to human obesity syndromes, such as Alström and Bardet-Biedl. Here we report the identification of a G --> T transversion in a candidate gene that abolishes a donor splice site in the 3' coding region and results in a larger transcript containing the unspliced intron. This alteration is predicted to replace the 44-carboxyterminal amino acids with a 20-amino-acid sequence not found in the wide-type protein. Additionally, a second, prematurely truncated transcript with the unspliced intron is observed in testis messenger RNA and a 2-3-fold increase in brain mRNA is observed in tubby mice compared to B6. The phenotype features of tubby mice may be the result of cellular apoptosis triggered by expression of the mutuated tub gene.