This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison
The tub gene
The Tub gene, also less comply known as rd-5, (NG_029912.1) is located on human chromosome 11p15.4. Two major mRNA splice variants exist for the Tub gene, namely TUB561 and TUB506. These two splice forms have a different exon 1 but share a common sequence beginning with exon 2 (Figure 1). The functional difference of these two variants is unknown as they show the same cellular localization, behavior, and function. [1] TUB561 was used throughout this site as the Tub gene.
The Tub gene is expressed in the cochlea, retina, and throughout the brain. Its high expression in the paraventricular (PVN), ventromedial (VMH), and arcuate nuclei (Arc) of the hypothalamus as well as the hippocampus (Hpc) supports the gene's role in body weight regulation and feeding behavior (Figure 2).[2]
The Tub gene is expressed in the cochlea, retina, and throughout the brain. Its high expression in the paraventricular (PVN), ventromedial (VMH), and arcuate nuclei (Arc) of the hypothalamus as well as the hippocampus (Hpc) supports the gene's role in body weight regulation and feeding behavior (Figure 2).[2]
The Tubby Mouse Mutation
A G to T transversion at the splice site between exons 11 and 12 is responsible for the tubby phenotype that includes adult-onset obesity in mice (Figure 3). This mutation leads to a longer transcript retaining the intron found between exons 11 and 12 and ultimately disrupts the highly conserved "tubby domain". [2,3] This mutation was shown to be a complete loss-of-function mutation as a knockout of the tub gene resulted in the same phenotype as seen in tubby mice. [4]
The mutant tub gene is still expressed in the same cellular locations but at higher levels than those seen in wild-type mice meaning that the mutation does not result in nonsense mediated decay by the cell. [1] It is interesting, however, that only very low levels of the TUB protein are found in tubby mutant mice indicating that the mutation must affect the stability and function of final protein itself. [4]
The mutant tub gene is still expressed in the same cellular locations but at higher levels than those seen in wild-type mice meaning that the mutation does not result in nonsense mediated decay by the cell. [1] It is interesting, however, that only very low levels of the TUB protein are found in tubby mutant mice indicating that the mutation must affect the stability and function of final protein itself. [4]
human polymorphisms in the tub Gene associated with body weight
While the tubby mouse has been a model for obesity for nearly twenty-five years, the role of Tub in human obesity is just beginning to be determined. Two single nucleotide polymorphisms (SNPs) in the C-terminal of Tub, namely rs2272382 and rs2272383, have been found to be associated with BMI in humans (Figure 4). One of these (rs2272382) is also more common and more likely to be homozygous in obese subjects, found in 37.3% of obese individuals, compared to only 31.1% in individuals of normal weight. [5] Middle aged women carrying the rs2272382 SNP also derived less energy from fat, more energy from carbohydrates, and have a higher glycemic load in their diet. These findings indicate that TUB may influence body weight and eating behaviors in humans. [6]
References
Cover Photo Credit
[1] He, W., Ikeda, S., Bronson, R.T., Yan, G., Nishina, P.M., North, M.A., and Naggert, J.K. (2000). GFP-tagged expression and immunohistochemical studies to determine the subcellular localization of the tubby gene family members. Molecular Brain Research, 81(1), 109. doi:10.1016/S0169-328X(00)00164-9.
[2] Kleyn, P.W., Fan, W., Kovats, S. G., et al. (1996). Identification and Characterization of the Mouse Obesity Gene tubby: A Member of a Novel Gene Family. Cell, 85(2), doi:10.1016/S0092-8674(00)81104-6.
[3] Noben-Trauth, K., Naggert, J.K., North, M.A, and Nishina, P.M. (1996). A candidate gene for the mouse mutation tubby. Nature, 380, 534. doi:10.1038/380534a0.
[4] Stubdal, H., Lynch, C.A., Moriarty, A., et al. (2000). Targeted Deletion of the tub Mouse Obesity Gene Reveals that tubby is a Loss-of-Function Mutation. Molecular and Cellular Biology, 20(3).
[5] Shiri-Sverdlov, R., Custers, A., et al. (2006). Identification of TUB as a Novel Candidate Gene Influencing Body Weight in Humans. Diabetes, 55 (2), 385, doi:10.2337/diabetes.55.02.06.db05-0997.
[6] vs Vliet-Ostaptchouk, J.V., Onland-Moret, N.C., Shiri-Sverdlov, R., et al. (2008). Polymorphisms of the TUB Gene Are Associated with Body Composition and Eating Behavior in Middle-Aged Women. PLoS ONE, 3(1), e1405. doi:10.1371/journal.pone.0001405.
[1] He, W., Ikeda, S., Bronson, R.T., Yan, G., Nishina, P.M., North, M.A., and Naggert, J.K. (2000). GFP-tagged expression and immunohistochemical studies to determine the subcellular localization of the tubby gene family members. Molecular Brain Research, 81(1), 109. doi:10.1016/S0169-328X(00)00164-9.
[2] Kleyn, P.W., Fan, W., Kovats, S. G., et al. (1996). Identification and Characterization of the Mouse Obesity Gene tubby: A Member of a Novel Gene Family. Cell, 85(2), doi:10.1016/S0092-8674(00)81104-6.
[3] Noben-Trauth, K., Naggert, J.K., North, M.A, and Nishina, P.M. (1996). A candidate gene for the mouse mutation tubby. Nature, 380, 534. doi:10.1038/380534a0.
[4] Stubdal, H., Lynch, C.A., Moriarty, A., et al. (2000). Targeted Deletion of the tub Mouse Obesity Gene Reveals that tubby is a Loss-of-Function Mutation. Molecular and Cellular Biology, 20(3).
[5] Shiri-Sverdlov, R., Custers, A., et al. (2006). Identification of TUB as a Novel Candidate Gene Influencing Body Weight in Humans. Diabetes, 55 (2), 385, doi:10.2337/diabetes.55.02.06.db05-0997.
[6] vs Vliet-Ostaptchouk, J.V., Onland-Moret, N.C., Shiri-Sverdlov, R., et al. (2008). Polymorphisms of the TUB Gene Are Associated with Body Composition and Eating Behavior in Middle-Aged Women. PLoS ONE, 3(1), e1405. doi:10.1371/journal.pone.0001405.
Site created by Rachael Baird.
Genetics 564 Assignment, Spring 2014
University of Wisconsin-Madison
Last Updated: 5-9-14
Genetics 564 Assignment, Spring 2014
University of Wisconsin-Madison
Last Updated: 5-9-14