Progression of Cochlear and Retinal Degeneration in the tubby (rd5) Mouse

Ohlemiller, Kevin K.; Hughes, Ruth M.; Lett, Jaclynn M.; Ogilvie, Judith Mosinger; Speck, Judith D.; Wright, James S.; Faddis, Brian T.

doi:10.1159/000259242

Cited by 51 publications

(32 citation statements)

References 11 publications

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“…Programmed cell death has been proposed as the cause of both retinal and cochlear degeneration in tubby mice (16,17), and this has now been formally demonstrated for retinal degeneration by our data as well as a very recent report (9). This result suggests that Tub function is important for the survival of retinal photoreceptor cells in the adult animal.…”

Section: Discussionsupporting

confidence: 85%

“…Earlier studies have shown that tubby mice exhibit early progressive retinal degeneration, possibly due to apoptosis (16,17). Photoreceptor cells, the main cell type lost, have been shown to express Tub (19).…”

Section: Downloaded Frommentioning

confidence: 99%

“…The tubby phenotype is inherited in an autosomal recessive manner and is characterized by late-onset weight gain accompanied by progressive retinal and cochlear degeneration (16,17). The combination of these phenotypes resembles human syndromes, such as Usher's (retinal and cochlear degeneration), BardetBiedl, and Alstrom's (obesity and sensory deficits).…”

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confidence: 99%

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

Stubdal

Lynch

Moriarty

et al. 2000

Molecular and Cellular Biology

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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 that tubby is a loss-of-function mutation of the tub gene 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.

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Section: Discussionsupporting

confidence: 85%

Section: Downloaded Frommentioning

confidence: 99%

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

Stubdal

Lynch

Moriarty

et al. 2000

Molecular and Cellular Biology

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“…4c). Although both hair and spiral ganglion cell degeneration first occur in tubby mice 15,16 by 20 weeks, functional defects assessed by ABR analysis are apparent at only 3 weeks 11,15 , suggesting that the degeneration of these cells might be a secondary event. As hearing loss in tubby mice was rescued by the 129P2/OlaHsd allele of Mtap1a, which is expressed specifically in the spiral ganglion cells, the tubby gene may significantly influence auditory signal transmission in these cells.…”

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confidence: 99%

Microtubule-associated protein 1A is a modifier of tubby hearing (moth1)

et al. 2002

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Once a mutation in the gene tub was identified as the cause of obesity, retinal degeneration and hearing loss in tubby mice 1-2 , it became increasingly evident that the members of the tub gene family (tulps) influence maintenance and function of the neuronal cell lineage [3][4][5][6] . Suggested molecular functions of tubby-like proteins include roles in vesicular trafficking 4,7 , mediation of insulin signaling 8 and gene transcription 9,10 . The mechanisms through which tub functions in neurons, however, have yet to be elucidated. Here we report the positional cloning of an auditory quantitative trait locus (QTL), the modifier of tubby hearing 1 gene (moth1) 11 , whose wildtype alleles from strains AKR/J, CAST/Ei and 129P2/OlaHsd protect tubby mice from hearing loss. Through a transgenic rescue experiment, we verified that sequence polymorphisms in the neuronspecific microtubule-associated protein 1a gene (Mtap1a) observed in the susceptible strain C57BL/6J (B6) are crucial for the hearing-loss phenotype. We also show that these polymorphisms change the binding efficiency of MTAP1A to postsynaptic density molecule 95 (PSD95), a core component in the cytoarchitecture of synapses. This indicates that at least some of the observed polymorphisms are functionally important and that the hearing loss in C57BL/6J-tub/ tub (B6-tub/tub) mice may be caused by impaired protein interactions involving MTAP1A. We therefore propose that tub may be associated with synaptic function in neuronal cells.The gene tub was first identified, through positional cloning efforts, as a gene with unknown function. A spontaneous mutation at the splice donor site in the last intron, which causes a replacement of the carboxy-terminal 44 amino acids with 24 amino acids that are not observed in the normal protein, leads to obesity associated with hyperinsulinemia and neurosensory deficits 1-2 . The fact that the targeted tub null allele 12 has the same phenotype as the spontaneous mutant confirms that this splice-site mutation is also the molecular basis for the spontaneous loss-of-function mutation.The moth1 locus is a major QTL that affects hearing in tubby mice. We previously showed that a single moth1 allele from strains AKR/J, CAST/EiJ or 129P2/OlaHsd was sufficient to protect B6-tub/tub mice from hearing loss 11 . The high level of significance for linkage of suppression of hearing loss (lod=33.4) observed on chromosome 2 suggested that finemapping by recombinant progeny testing 13 could be applied to the moth1 locus. We collected a total of 1,780 meioses, of which 1,330 came from an F2 (B6-tub/tub × AKR) intercross and 450 from an F2 (B6-tub/tub × CAST.B6-tub/tub) intercross (Fig. 1a). All animals recombinant with respect to the critical region were progeny-tested to confirm the Correspondence should be addressed to P.M.N. (pmn@jax.org). presence of the protective moth1 allele in the recombinant region (Fig. 1b). The minimal moth1 region is 0.17 ± 0.1 cM and flanked by markers D2Dcr11 and D2Pjn298. We assembled a physical contig...

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“…Tubby, an autosomal recessive syndrome in mice, is characterized by maturity-onset obesity, insulin resistance, infertility, and progressive cochlear and retinal degeneration (1)(2)(3). The tubby phenotype resembles human sensory/obesity syndromes such as Alstrom's and Bardet/Biedl that are characterized by combined cochlear hair cell and retinal photoreceptor loss accompanied by infertility and moderate late-onset obesity (4 -6).…”

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confidence: 99%