Alternative titles; symbols
HGNC Approved Gene Symbol: TUB
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:8,019,059-8,106,243 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | ?Retinal dystrophy and obesity | 616188 | Autosomal recessive | 3 |
The mouse 'tubby' phenotype is characterized by pigmentary retinopathy, obesity, mental retardation, hypogenitalism, and polysyndactyly. Noben-Trauth et al. (1996) identified a candidate gene for mouse tubby on the basis of positional cloning. The candidate gene in tubby mice differed consistently from that in normal mice with respect to transcript size. Sequence analysis of the candidate gene revealed a G-to-T transversion that abolished the donor splice site in the 3-prime coding region, leading to a larger transcript in tubby. The transcript was 6.6 kb in tubby versus 6.3 kb in B6 mice. Sequence analysis of the candidate gene revealed that the 200 amino acids at the C terminus show 62% identity to a mouse phosphodiesterase. Because mutations in the cGMP phosphodiesterase genes (e.g., 180071) are known to cause retinal degeneration through photoreceptor cell apoptosis, and because the retinal degeneration in tubby has hallmarks of apoptosis, Noben-Trauth et al. (1996) postulated that mutations in the phosphodiesterase-like candidate tubby gene lead to phenotypic effects through apoptotic events.
Kleyn et al. (1996) also used positional cloning to identify a gene responsible for the tubby phenotype in mice. Tubby mutants were found to produce a larger transcript for this candidate gene (approximately 7.5 kb) than that produced by normal mice (7 kb). The RNA transcript in tubby was also 4-fold more abundant than the transcript in normal mice. The larger transcript in the mutant mice was due to a G-to-T transversion in a single splice donor site, leading to the substitution of 44 C-terminal amino acids, with 24 intron-encoded amino acids. The mutation identified by Kleyn et al. (1996) is apparently the same as that described by Noben-Trauth et al. (1996). Northern blot analysis revealed that the candidate gene was expressed primarily in brain, particularly in the paraventricular, ventromedial, and arcuate nuclei of the hypothalamus. Kleyn et al. (1996) showed that strain-specific differences occurred in the relative abundance of alternate splice products. Alternate splice products differed with respect to the presence or absence of exon 5. Kleyn et al. (1996) demonstrated that this splice variation correlates with an intron length polymorphism and proposed this Tub allele as a candidate for the obesity quantitative trait locus on mouse chromosome 7. See also UCP2 (601693).
Kleyn et al. (1996) isolated the human homolog of the mouse Tub gene and determined that the deduced protein shares 94% sequence identity with the mouse protein, with highest conservation in the C terminus.
Sahly et al. (1998) reported the Tub gene expression pattern in embryonic, fetal, and adult mouse tissues as determined by Northern blot analysis and in situ hybridization. In mouse embryos, Tub is expressed selectively in differentiating neurons of the central and peripheral nervous systems, starting at 9.5 days after conception. In adult mice, Tub is transcribed in several major brain areas, including cerebral cortex, hippocampus, several nuclei of the hypothalamus controlling feeding behavior, in the spiral ganglion of the inner ear, and in photoreceptor cells of the retina. These structures contain potential cellular targets of tubby mutation-induced pathogenesis.
Borman et al. (2014) used immunohistochemistry to analyze distribution of TUB in the human retina and found strong expression in the nuclei of the ganglion cell layer as well as the inner and outer nuclear layer, with moderate staining in the inner segment of photoreceptor cells. Double immunofluorescence labeling of TUB and molecular markers of ciliary compartments revealed localization of TUB at the base of the photoreceptor cilium and the ciliary rootlet, projecting through the inner segment of the photoreceptor cell.
Crystal Structure
Boggon et al. (1999) determined the crystal structure of the core domain of mouse tubby at a resolution of 1.9 angstroms.
Coleman and Eicher (1990) mapped the mouse 'tubby' locus to chromosome 7, close to the Hbb gene (141900). Jones et al. (1992) found that the Tub gene was located 2.4 +/- 1.4 cM from Hbb and suggested that the human Tub homolog maps to a region of syntenic homology on 11p15.
From a study of the spatial and temporal coincidences of gene expression patterns in mice, Sahly et al. (1998) suggested a similarity of function for Tub with carboxypeptidase E (CPE; 114855), which is the site of a null mutation in the fat/fat mouse, prohormone convertase (PCSK1; 162150), which is involved in the pathogenesis of one form of gross obesity, and other pro-proteases. The findings were also considered compatible with the alternative hypothesis that Tub is a neuropeptide involved in numerous neurophysiologic and endocrine functions regulating feeding behavior and sensory perception.
From primarily structural clues, Boggon et al. (1999) devised experiments, the results of which suggested that tubby-like proteins are a unique family of bipartite transcription factors. The tubby C terminus is able to bind double-stranded DNA, while the N-terminal regions of tubby and TULP1 (602280) potently activate transcription.
Santagata et al. (2001) demonstrated that tubby functions in signal transduction from heterotrimeric G protein-coupled receptors. Tubby localizes to the plasma membrane by binding phosphatidylinositol 4,5-bisphosphate through its C-terminal 'tubby domain.' X-ray crystallography revealed the atomic-level basis of this interaction and implicated tubby domains as phosphorylated phosphatidylinositol-binding factors. Receptor-mediated activation of G protein alpha-q (GNAQ; 600998) releases tubby from the plasma membrane through the action of phospholipase C-beta (see 604114), triggering translocation of tubby to the cell nucleus. The localization of tubby-like protein-3 (TULP3; 604730) is similarly regulated. Santagata et al. (2001) concluded that tubby proteins function as membrane-bound transcription regulators that translocate to the nucleus in response to phosphoinositide hydrolysis, providing a direct link between G protein signaling and the regulation of gene expression.
In 3 affected sibs from a consanguineous Caucasian family from the United Kingdom with retinal dystrophy and obesity (RDOB; 616188), Borman et al. (2014) identified homozygosity for a 2-bp deletion in the TUB gene (601197.0001) that segregated with disease.
Heckenlively et al. (1995) described a mouse mutant that they suggested might be a mouse model of Usher syndrome type IC. The mutant locus, designated rd5 (Tub), showed linkage on chromosome 7 to Hbb (141900), which is located in a region with homology of synteny to human 11p15. The electroretinogram in homozygous rd5/rd5 mice was never normal, with reduced amplitudes that extinguished by 6 months. At 3 weeks, auditory-evoked response testing demonstrated increased hearing thresholds above controls of about 30 decibels (dB) that worsened to about 45 dB by 6 months. By indirect ophthalmoscopy, Heckenlively et al. (1995) observed retinal abnormalities by 6 weeks: arterial attenuation, venous dilation, and a granule appearance to the retinal pigment epithelium. By 5 months, severe retinal vessel attenuation and sheathing, focal and diffuse loss of pigment epithelium, and patches of pigment deposits were obvious.
Ikeda et al. (1999) performed a quantitative trait locus (QTL) analysis for auditory brainstem response (ABR) thresholds, which indicate hearing ability, in tubby mice from several F2 intercrosses. They identified a major QTL, which they designated 'modifier of tubby hearing-1' (moth1), that mapped to chromosome 2 with a lod score of 33.4 in the AKR intercross and of 6.0 in the CAST intercross. This QTL was responsible for 57% and 43% of ABR threshold variance, respectively, in each strain combination. In addition, a C57BL/6J congenic line carrying a segment encompassing the described QTL region also exhibited normal hearing ability when made homozygous for tubby. Ikeda et al. (1999) hypothesized that C57BL/6J mice carry a recessive mutation of the moth1 gene that interacts with the tub mutation to cause hearing loss in tub/tub mice. One allele from either AKR/J, CAST/Ei, or 129/Ola was sufficient to protect C57BL/6J tub/tub mice from hearing loss. It remained to be determined how the moth1 gene affects the other tubby phenotypes, such as retinal degeneration and obesity. Ikeda et al. (2002) reported the positional cloning of the auditory QTL modifying TUB1 as the MAP1A gene (600178). Through a transgenic rescue experiment, Ikeda et al. (2002) verified that sequence polymorphisms in the neuron-specific MAP1A gene observed in the susceptible strain C57BL/6J are crucial for the hearing loss phenotype. Ikeda et al. (2002) also showed that these polymorphisms changed the binding efficiency of MAP1A to postsynaptic density molecule PSD95 (602887), a core component in the cytoarchitecture of synapses. Ikeda et al. (2002) concluded that at least some of the observed polymorphisms are functionally important and that the hearing loss in C57BL/6J-tub/tub mice may be caused by impaired protein interactions involving MAP1A. They proposed that TUB may be associated with synaptic function in neuronal cells.
In 3 affected sibs from a consanguineous Caucasian family from the United Kingdom with retinal dystrophy and obesity (RDOB; 616188), Borman et al. (2014) identified homozygosity for a 2-bp deletion (c.1194_1195delAG), causing a frameshift predicted to result in a premature termination codon (Arg398SerfsTer9). The mutation, which was present in heterozygosity in the unaffected parents and an unaffected sib, was not found in more than 6,000 exomes in the NHLBI Exome Variant Server database. Functional analysis in transfected HEK293 cells showed that the mutant TUB is expressed at a reduced level compared to wildtype and is mislocalized, being detected primarily at the nucleus, whereas wildtype was detected within the cytoplasm and at the plasma membrane. Subcellular fractionation confirmed the mislocalization, and also revealed that mutant but not wildtype TUB was found in the insoluble fraction of the pellet, suggesting that the mutant may form aggregates within cells.
Boggon, T. J., Shan, W.-S., Santagata, S., Myers, S. C., Shapiro, L. Implication of tubby proteins as transcription factors by structure-based functional analysis. Science 286: 2119-2125, 1999. [PubMed: 10591637] [Full Text: https://doi.org/10.1126/science.286.5447.2119]
Borman, A. D., Pearce, L. R., Mackay, D. S., Nagel-Wolfrum, K., Davidson, A. E., Henderson, R., Garg, S., Waseem, N. H., Webster, A. R., Plagnol, V., Wolfrum, U., Farooqi, I. S., Moore, A. T. A homozygous mutation in the TUB gene associated with retinal dystrophy and obesity. Hum. Mutat. 35: 289-293, 2014. [PubMed: 24375934] [Full Text: https://doi.org/10.1002/humu.22482]
Coleman, D. L., Eicher, E. M. Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J. Hered. 81: 424-427, 1990. [PubMed: 2250094] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a111019]
Heckenlively, J. R., Chang, B., Erway, L. C., Peng, C., Hawes, N. L., Hageman, G. S., Roderick, T. H. Mouse model for Usher syndrome: linkage mapping suggests homology to Usher type I reported at human chromosome 11p15. Proc. Nat. Acad. Sci. 92: 11100-11104, 1995. [PubMed: 7479945] [Full Text: https://doi.org/10.1073/pnas.92.24.11100]
Ikeda, A., Zheng, Q. Y., Rosenstiel, P., Maddatu, T., Zuberi, A. R., Roopenian, D. C., North, M. A., Naggert, J. K., Johnson, K. R., Nishina, P. M. Genetic modification of hearing in tubby mice: evidence for the existence of a major gene (moth1) which protects tubby mice from hearing loss. Hum. Molec. Genet. 8: 1761-1767, 1999. [PubMed: 10441341] [Full Text: https://doi.org/10.1093/hmg/8.9.1761]
Ikeda, A., Zheng, Q. Y., Zuberi, A. R., Johnson, K. R., Naggert, J. K., Nishina, P. M. Microtubule-associated protein 1A is a modifier of tubby hearing (moth1). Nature Genet. 30: 401-405, 2002. [PubMed: 11925566] [Full Text: https://doi.org/10.1038/ng838]
Jones, J. M., Meisler, M. H., Seldin, M. F., Lee, B. K., Eicher, E. M. Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7. Genomics 14: 197-199, 1992. [PubMed: 1358794] [Full Text: https://doi.org/10.1016/s0888-7543(05)80308-8]
Kleyn, P. W., Fan, W., Kovats, S. G., Lee, J. J., Pulido, J. C., Wu, Y., Berkemeier, L. R., Misumi, D. J., Holmgren, L., Charlat, O., Woolf, E. A., Tayber, O., and 15 others. Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell 85: 281-290, 1996. [PubMed: 8612280] [Full Text: https://doi.org/10.1016/s0092-8674(00)81104-6]
Noben-Trauth, K., Naggert, J. K., North, M. A., Nishina, P. M. A candidate gene for the mouse mutation tubby. Nature 380: 534-538, 1996. [PubMed: 8606774] [Full Text: https://doi.org/10.1038/380534a0]
Sahly, I., Gogat, K., Kobetz, A., Marchant, D., Menasche, M., Castel, M.-N., Revah, F., Dufier, J.-L., Guerre-Millo, M., Abitbol, M. M. Prominent neuronal-specific tub gene expression in cellular targets of tubby mice mutation. Hum. Molec. Genet. 7: 1437-1447, 1998. [PubMed: 9700199] [Full Text: https://doi.org/10.1093/hmg/7.9.1437]
Santagata, S., Boggon, T. J., Baird, C. L., Gomez, C. A., Zhao, J., Shan, W. S., Myszka, D. G., Shapiro, L. G-protein signaling through tubby proteins. Science 292: 2041-2050, 2001. [PubMed: 11375483] [Full Text: https://doi.org/10.1126/science.1061233]