Microtubule-associated protein 1A is a modifier of tubby hearing (moth1)
Microtubule-associated protein 1A is a modifier of tubby hearing (moth1)
复制标题
DOI：
10.1038/ng838
复制
发表时间：
2002-04-01
期刊：
影响因子：
30.8
通讯作者：
Nishina, PM
中科院分区：
文献类型：
--
作者：
Ikeda, A;Zheng, QY;Nishina, PM
一旦基因tub中的突变被鉴定为肥胖小鼠中肥胖、视网膜变性和听力损失的原因（1-2），tub基因家族（tulps）的成员影响神经元细胞谱系的维持和功能变得越来越明显（3-6）。推测的管状蛋白的分子功能包括在囊泡运输（4，7）、胰岛素信号传导（8）和基因转录（9，10）中的作用。然而，tub在神经元中发挥作用的机制还有待阐明。在这里，我们报告了一个听觉数量性状基因座（QTL）的定位克隆，该基因座是tubby听力1基因（moth 1）的修饰基因（11），其来自品系AKR/J、CAST/Ei和129 P2/OlaHsd的野生型等位基因保护tubby小鼠免受听力损失。通过转基因拯救实验，我们证实了在易感菌株C57 BL/6 J（B6）中观察到的神经元特异性微管相关蛋白1a基因（Mtap 1a）的序列多态性对听力损失表型至关重要。我们还表明，这些多态性改变了MTAP 1A的结合效率突触后密度分子95（PSD 95），在突触的细胞结构的核心组成部分。这表明至少一些观察到的多态性在功能上是重要的，并且C57 BL/6 J-tub/tub（B6-tub/tub）小鼠的听力损失可能是由涉及MTAP 1A的蛋白质相互作用受损引起的。因此，我们认为tub可能与神经元细胞的突触功能有关。
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(3-6). 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 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.