A MUTATION in the tub gene causes maturity-onset obesity, insulin resi
stance(1), and sensory (d)eficits(2,3). In contrast to the rapid juven
ile-onset weight gain seen in diabetes (db) and obese (ob) mice, obesi
ty in tubby mice develops gradually, and strongly resembles the late-o
nset obesity seen in the human population. Excessive deposition of adi
pose tissue eventually leads to a twofold increase of body weight. Tub
by mice also suffer retinal degeneration and neurosensory hearing loss
(2,3). The tripartite character of the tubby phenotype shows striking
similarity to human obesity syndromes, such as Alstrom(4) and Bardet-B
iedl(5). Here we report the identification of a G --> T transversion i
n a candidate gene that abolishes a donor splice site in the 3' coding
region and results in a larger transcript containing the unspliced in
tron. This alteration is predicted to replate the 44-carboxy-terminal
amino acids with a 20-amino-acid sequence not found in the wild-type p
rotein. Additionally, a second, prematurely truncated transcript with
the unspliced intron is observed in testis messenger RNA and a 2-3-fol
d increase in brain mRNA is observed in tubby mice compared to B6. The
phenotypic features of tubby mice may be the result of cellular apopt
osis triggered by expression of the mutated tub gene.