Disease relevance of Tub

• The tubby mouse, which shows late-onset obesity and neurosensory deficits, arises from a mutation in the Tub gene [1].
• Once a mutation in the gene tub was identified as the cause of obesity, retinal degeneration and hearing loss in tubby mice, it became increasingly evident that the members of the tub gene family (tulps) influence maintenance and function of the neuronal cell lineage [2].
• However, in contrast to tubby mice, Tulp1 (-/-)mice exhibited normal hearing ability and, surprisingly, normal body weight despite the fact that both TUB and TULP1 are expressed in the same neurons within the hypothalamus in areas known to be involved in feeding behavior and energy homeo stasis [3].
• Tubby mice also suffer retinal degeneration and neurosensory hearing loss [4].
• For insulin levels, 15 of 16 recombinant inbred strains were concordant with a region that contains the tubby mutation that results in hyperinsulinemia [5].

High impact information on Tub

• Tubby mice and individuals with Bardet-Biedl syndrome have defects in ciliated neuron function and obesity, suggesting an as-yet unknown metabolic signaling axis from ciliated neurons to fat storage tissues [6].
• Here we report the positional cloning of an auditory quantitative trait locus (QTL), the modifier of tubby hearing 1 gene (moth1), whose wildtype alleles from strains AKR/J, CAST/Ei and 129P2/OlaHsd protect tubby mice from hearing loss [2].
• A recessive mutation in the tub gene causes obesity, deafness and retinal degeneration in tubby mice [7].
• Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family [8].
• The mutated gene responsible for the tubby obesity phenotype has been identified by positional cloning [8].

Chemical compound and disease context of Tub

• It is demonstrated here that thyroid hormone regulates in vivo and in vitro the tub gene, which when mutated in tubby mice causes obesity, insulin resistance and sensory deficits [9].

Biological context of Tub

• To test the hypothesis that mutations within other members of this gene family would lead to similar phenotypes as observed in tubby mice, and hence have similar functional properties, we have generated null mutants of the tubby-like protein ( Tulp ) 1 gene by homologous recombination [3].
• Mice carrying different tulp1/tubby allele combinations were examined by histology, electroretinograms (ERGs), and immunofluorescence microscopy [10].
• Here we show that tubby functions in signal transduction from heterotrimeric GTP-binding protein (G protein)-coupled receptors [11].
• Tubby, an autosomal recessive mutation, mapping to mouse chromosome 7, was recently found to be the result of a splicing defect in a novel gene with unknown function [12].
• We report a mouse model of type I Usher syndrome, rd5, whose linkage on mouse chromosome 7 to Hbb and tub has homology to human Usher I reported on human chromosome 11p15 [13].

Anatomical context of Tub

• Comparison of disease phenotypes in the single and double mutants suggests that TULP1 and Tubby are not functionally interchangeable in photoreceptors nor do they form an obligate functional complex [10].
• 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 [4].
• Tubby localizes to the plasma membrane by binding phosphatidylinositol 4,5-bisphosphate through its carboxyl terminal "tubby domain." X-ray crystallography reveals the atomic-level basis of this interaction and implicates tubby domains as phosphorylated-phosphatidyl- inositol binding factors [11].
• To determine whether this is a general feature of obesity, we studied [(3)H]oleate uptake by adipocytes and hepatocytes from 1) homozygous male obese (ob), diabetic (db), fat (fat), and tubby (tub) mice and from 2) male Harlan Sprague-Dawley rats fed for 7 weeks a diet containing 55% of calories from fat [14].
• We have examined the cochleas of adult tubby mice using light microscopy [15].

Associations of Tub with chemical compounds

• Similarly, an age and body mass-dependent induction (about 30-fold) of neuropeptide Y (NPY) mRNA was observed in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei of the tubby mice [16].
• Compared with control mice, obese, diabetes, tubby, and lethal yellow mice had triglyceride levels that were elevated 1.5-fold to twofold, but fat mice had triglyceride levels similar to those of controls [17].
• Natural killer (NK) cell activity is inhibited by the adenosine analogue tubercidin (Tub) and stimulated by the deoxyadenosine analogue 2-fluoro-1-beta-D-arabinofuranosyladenine 5'-monophosphate (F-ara-AMP) in the spleen lymphocytes from mice treated with the drugs in vivo (T. Priebe et al., Cancer Res., 48:4799, 1988) [18].
• In concordance with this, tubby mice show higher excretion of ketone bodies and accumulation of glycogen in the liver [19].
• Quantitation of liver mRNA levels shows that, during the transition from light to dark period, tubby mice fail to induce glucose-6-phosphate dehydrogenase (G6pdh), the rate-limiting enzyme in the pentose phosphate pathway that normally supplies NADPH for de novo fatty acid synthesis and glutathione reduction [19].

Other interactions of Tub

• Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7 [20].
• The hearing modifier (Moth1) of tubby (Tub(tub)) mutant mice was shown to be a strain variant of the Mtap1a gene [21].
• However, NPY mRNA in the ARC was decreased by approximately 30 to 40% in both juvenile and mature tubby mice [16].
• In comparison with the wild-type controls, a significant reduction (20%) of pro-opiomelanocortin (POMC) mRNA expression was observed in the arcuate nucleus (ARC) of the mature, obese but not in the juvenile, non-obese tubby mice [16].
• 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 [22].

Analytical, diagnostic and therapeutic context of Tub

• METHODS: In situ hybridization using riboprobes specific for each tubby gene family member and immunohistochemistry for TUB and TULP1 were performed to determine their expression patterns in the retina of tubby and wild-type control mice [23].
• The terminal dUTP nick-end labeling (TUNEL) assay was performed to detect apoptotic cells in the retina of tubby and wild-type control mice [23].
• Finally, we report tubby expression in mouse brain by in situ hybridization and by immunohistochemistry with polyclonal antibodies [24].
• PURPOSE: The tubby mouse, previously suggested as an animal model for the human Usher Syndrome type I, was used in an analysis of pathophysiological processes leading to the inherited retinal degeneration, also shown in Usher syndrome patients [25].

References