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A candidate gene for the mouse mutation tubby

Naturevolume 380pages534538 (1996) | Download Citation



A MUTATION in the tub gene causes maturity-onset obesity, insulin resistance1, and sensory deficits2,3. 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 loss2,3. The tripartite character of the tubby phenotype shows striking similarity to human obesity syndromes, such as Alström4 and Bardet-Biedl5. 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-carboxy-terminal amino acids with a 20-amino-acid sequence not found in the wild-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 phenotypic features of tubby mice may be the result of cellular apoptosis triggered by expression of the mutated tub gene.

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  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, USA

    • Konrad Noben-Trauth
    • , Juergen K. Naggert
    •  & Patsy M. Nishina
  2. Sequana Therapeutic Inc., La Jolla, California, 92037, USA

    • Michael A. North


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