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

Nature genetics | Apr 1, 2002

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. Suggested molecular functions of tubby-like proteins include roles in vesicular trafficking, mediation of insulin signaling and gene transcription. 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), 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 neuron-specific 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.

Pubmed ID: 11925566 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Alleles | Animals | Cell Line | Cloning, Molecular | DNA, Complementary | Gene Library | Genetic Markers | Guanylate Kinases | Immunoblotting | Insulin | Intracellular Signaling Peptides and Proteins | Membrane Proteins | Mice | Mice, Inbred C57BL | Mice, Transgenic | Microscopy, Fluorescence | Microtubule-Associated Proteins | Models, Genetic | Nerve Tissue Proteins | Neurons | Phenotype | Polymorphism, Genetic | Precipitin Tests | Protein Binding | Protein Structure, Tertiary | Proteins | Quantitative Trait, Heritable | Reverse Transcriptase Polymerase Chain Reaction | Signal Transduction | Synapses | Transcription, Genetic | Transgenes

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Associated grants

  • Agency: NIDCD NIH HHS, Id: R01 DC004301-01
  • Agency: NIDCD NIH HHS, Id: R01 DC005827
  • Agency: NIDCD NIH HHS, Id: R01 DC005827-01
  • Agency: NEI NIH HHS, Id: R01 EY016501-06
  • Agency: NIDDK NIH HHS, Id: R01 DK046977-10
  • Agency: NEI NIH HHS, Id: R01 EY016501
  • Agency: NIDCD NIH HHS, Id: R03 DC004376-01A1
  • Agency: NIDDK NIH HHS, Id: R01 DK046977-07
  • Agency: NIDDK NIH HHS, Id: R01 DK046977
  • Agency: NIDCD NIH HHS, Id: R01 DC004301
  • Agency: NIDCD NIH HHS, Id: R03 DC004376

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