Targeted Deletion of the tub Mouse Obesity Gene Reveals that tubby Is a Loss-of-Function Mutation

Abstract

The mouse tubby phenotype is characterized by maturity-onset obesity accompanied by retinal and cochlear degeneration. A positional cloning effort to find the gene responsible for this phenotype led to the identification of tub, a member of a novel gene family of unknown function. A splice defect mutation in the 3′ end of the tub gene, predicted to disrupt the C terminus of the Tub protein, has been implicated in the genesis of the tubby phenotype. It is not clear, however, whether the Tub mutant protein retains any biological activity, or perhaps has some dominant function, nor is it established that the tubby mutation is itself responsible for all of the observed tubby phenotypes. To address these questions, we generated tub-deficient mice and compared their phenotype to that of tubby mice. Our results demonstrate thattubby is a loss-of-function mutation of the tubgene and that loss of the tub gene is sufficient to give rise to the full spectrum of tubby phenotypes. We also demonstrate that loss of photoreceptors in the retina of tubby and tub-deficient mice occurs by apoptosis. In addition, we show that Tub protein expression is not significantly altered in the ob, db, or melanocortin 4 receptor-deficient mouse model of obesity.

ACKNOWLEDGMENTS

We thank Rene Devos and colleagues at Roche-Gent Research Institute for the anti-Tub sera. We thank Lou Tartaglia, Jim Lillie, Frank Lee, and Bob Tepper for helpful discussions and advice, Suzy Dembsky for help with tissue dissection, Pei Ge and Michael Donovan for pathology, and Tanya Macek for genotyping. We are also grateful to all the members of Millennium's Metabolic Diseases Biology team for helpful and stimulating discussions.

This work was partly supported by Hoffmann-La Roche, Inc.