Myosin XVA and Other Genes Essential for Stereocilia Morphogenesis

肌球蛋白 XVA 和其他对于立体纤毛形态发生至关重要的基因

• 批准号: 7966974
• 负责人: Thomas Friedman
• 金额: $ 87.25万
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7966974
• 关键词: 17p11.2; Actins; Amino Acids; Auditory; Auditory system; Binding; Biochemistry; Biological; Chromosomes; Exons; Family; Genes; Genetic; Head; Hearing; Human; Light; Link; Molecular Biology; Molecular Motors; Morphogenesis; Motor; Mus; Mutation; Myosin ATPase; Neck; Play; Protein Isoforms; Proteins; RNA Splicing; Research Design; Role; Stereocilium; Tail; base; congenital deafness; deafness; myosin XVA; yeast two hybrid system

Mutations of myosin XVA in humans and mice cause profound congenital deafness. Myosins are actin based molecular motors that have a conserved head (motor) and neck (light chain binding motifs) and highly divergent tail domains. The MYO15A tail contains several domains which are candidates for protein interaction motifs. The identification of proteins that functionally interact with MYO15 may provide the best means of determining the role of MYO15A in the auditory system. In addition, interacting proteins are themselves likely to play crucial roles in hearing and would be strong candidates for proteins encoded by deafness loci. We are therefore using a yeast two hybrid system to identify proteins that interact with the myosin XVA. Genes that encode poteins that interact with myosin XVA from these two screens will be further examined for biological relevance. Whirlin is one such partner of myosin XVa and is necessary for stereocilia elongation and staircase formation (Belyantseva et al. 2005). Two years ago we identified mutations in families segregating DFNB3 deafness due to mutations in exon 2 of MYO15A (Nal et al., 2007). This large exon alone encodes about 1,200 amino acids. The auditory function of the isoform of Myo15a that includes the long (1220 amino acid residues) N-terminus is being pursued using genetics, molecular biology and biochemistry.

人类和小鼠的肌球蛋白 XVA 突变会导致严重的先天性耳聋。肌球蛋白是基于肌动蛋白的分子马达，具有保守的头部（马达）和颈部（轻链结合基序）以及高度分化的尾部结构域。 MYO15A 尾部包含多个结构域，这些结构域是蛋白质相互作用基序的候选结构域。与 MYO15 功能性相互作用的蛋白质的鉴定可能提供确定 MYO15A 在听觉系统中的作用的最佳方法。此外，相互作用的蛋白质本身可能在听力中发挥关键作用，并且是耳聋基因座编码的蛋白质的有力候选者。因此，我们使用酵母两种杂交系统来鉴定与肌球蛋白 XVA 相互作用的蛋白质。将进一步检查这两个筛选中编码与肌球蛋白 XVA 相互作用的蛋白的基因的生物学相关性。 Whirlin 是肌球蛋白 XVa 的伙伴之一，对于静纤毛伸长和阶梯形成是必需的 (Belyantseva et al. 2005)。两年前，我们在分离 DFNB3 耳聋的家族中发现了由于 MYO15A 外显子 2 突变导致的突变（Nal 等，2007）。 仅这个大外显子就编码约 1,200 个氨基酸。包括长（1220 个氨基酸残基）N 末端的 Myo15a 同工型的听觉功能正在利用遗传学、分子生物学和生物化学进行研究。