Identification and characterisation of a new gene that is mutated in an autosomal recessive form of nonsyndromic hearing impairment

我以前的DFG研究提案的目的是“识别和表征一个新的基因，是突变的常染色体隐性形式的非综合征性听力障碍”是找到并初步表征一个新的基因，这是突变的常染色体隐性形式的听力障碍，称为DFNB 42。在2009/2010年DFG资助期间，我已经确定了ILDR 1基因突变是DFNB 42位点听力障碍的原因。因此，ILDR 1是一个新的耳聋基因。这项研究的结果发表在2011年1月的《美国人类遗传学杂志》上。在接下来的2年中，我将在此提交研究经费申请，我计划更好地描述ILDR 1在内耳和生理听觉过程中的作用。ILDR 1编码一种功能未知的跨膜受体。我们以前已经表明，通过mRNA原位杂交，小鼠直系同源Ildr 1的表达在毛细胞和支持细胞的耳蜗和前庭器官的毛细胞。我计划通过免疫化学方法对小鼠内耳中的Ildr 1蛋白进行精确定位，以扩展这些结果。此外，我将寻找ILDR 1配体和相互作用的合作伙伴，通过使用蛋白质生物化学的新方法，相互作用的合作伙伴，可以确定不仅为胞质，但也为跨膜蛋白。最后，我计划通过敲低模式生物斑马鱼中ILDR 1旁系同源物的表达来创建DFNB 42的第一个动物模型，这将有助于更好地理解ILDR 1对脊椎动物听力的贡献。这些分析将有助于更好地理解ILDR 1在听力和耳聋中的作用，更广泛地说，有助于更深入地理解听力本身的复杂过程。

The aim of my previous DFG research proposal entitled “Identification and characterisation of a new gene that is mutated in an autosomal recessive form of nonsyndromic hearing impairment“ was to find and initially characterize a novel gene which is mutated in an autosomal-recessive form of hearing impairment, called DFNB42. During the 2009/2010 funding period of this DFG grant I have identified mutations of the ILDR1 gene as causative for hearing impairment at the DFNB42 locus. Thus, ILDR1 is a novel deafness gene. The results of this study have been published in the January 2011 issue of the Amercian Journal of Human Genetics. In the 2 years of follow-up for which I present the grant application here, I plan to better characterize the role that ILDR1 plays in the inner ear and in the pysiological hearing process. ILDR1 encodes a putative transmembrane receptor of unknown function. We have previously shown by mRNA in situ hybridization that the mouse ortholog Ildr1 is expressed in hair cells and supporting cells of the cochlea and in hair cells of the vestibular organ. I plan to extend these results by pecisely localizing the Ildr1 protein in the mouse inner ear by immunochemistry. Moreover, I will search for ILDR1 ligands and interaction partners by using novel methods of protein biochemistry by which interaction partners can be identified not only for cytosolic but also for transmembrane proteins. Finally, I plan to create a first animal model for DFNB42 by knocking down the expression of ILDR1 paralogs in the model organism, zebrafish, which will allow for a better understanding of the the contribution of ILDR1 to hearing in vertebrates. These analyses will hopefully contribute to a better understanding of the role that ILDR1 plays in hearing and deafness and more generally to a deeper understanding of the complex process of hearing itself.