可变剪接-无义突变介导mRNA降解参与GJB2复合杂合突变致聋及调控

Current hot researches on otology focus on genetic pathology and gene therapy for deafness. As the most common gene responsible for hereditary hearing impairment, GJB2 compound heterozygous mutations constitute a large proportion. These mutations were characterized with phenotype heterozygosity and pathogenesis uncertainty, which may impede effective and accurate prenatal intervention. So far, effectively guide the prevention of deafness are still unavailable. Alternative splicing - nonsense-mediated mRNA degradation studies provide insight into gene diversity. We herein propose “compound heterozygous GJB2 gene mutations- alternatively spliced-nonsense-mediated mRNA degradation-CX26 functional alteration- deafness phenotype modification”after comprehensive literature reviewing. The project aims to study the functional role of alternatively spliced-nonsense-mediated mRNA degradation in GJB2 compound heterozygous mutation, as well as regulating alternative splicing - a nonsense mutation-mediated mRNA degradation to alleviate or inhibit residual functional GJB2 mRNA degradation, therefore to reverse or reduce the incidence of deafness. The project studies the mechanism of GJB2 compound heterozygous mutations from mRNA splicing aspect, to provide a new perspective on the basis of gene therapy for deafness, and has important theoretical significance and potential clinical value.

耳聋的遗传研究和基因治疗是目前耳科领域研究的热点。GJB2为遗传性耳聋主要致聋基因。GJB2基因复合杂合突变比例较高，其听力表型的多样性和病理机制仍不确定，阻碍临床有效和确切的产前干预，迄今仍无法进行有效的耳聋预防指导。可变剪接-无义突变介导mRNA降解研究为基因突变多样性提供新的思路和线索。结合文献，我们提出GJB2基因复合杂合突变-可变剪接无义突变介导mRNA降解-CX26蛋白功能变化-耳聋表型修饰。本项目拟通过研究可变剪接-无义突变介导mRNA降解在GJB2复合杂合突变中的作用，以及调节可变剪接-无义突变介导mRNA降解水平，探讨可能减缓或抑制残留的功能性GJB2突变体mRNA的降解，逆转耳聋的发生或减轻耳聋的损伤的科学问题。本项目从mRNA剪接方向研究GJB2基因复合杂合突变致聋的制，为耳聋的基因治疗提供新的角度和依据，具有重要的理论意义及潜在的临床应用价值。

耳聋的遗传研究和基因治疗是目前耳科领域研究的热点。GJB2为遗传性耳聋主要致聋基因 。GJB2基因复合杂合突变比例较高，其听力表型的多样性和病理机制仍不确定，阻碍临床有效 和确切的产前干预，迄今仍无法进行有效的耳聋预防指导。可变剪接-无义突变介导mRNA降解 研究为基因突变多样性提供新的思路和线索。结合文献，我们提出GJB2基因复合杂合突变-可 变剪接无义突变介导mRNA降解-CX26蛋白功能变化-耳聋表型修饰。本项目通过研究可变剪接 -无义突变介导mRNA降解在GJB2复合杂合突变中的作用，以及调节可变剪接-无义突变介导mRNA 降解水平，探讨了可能减缓或抑制残留的功能性GJB2突变体mRNA的降解，逆转耳聋的发生或减轻耳聋的损伤的科学问题。本项目从mRNA剪接方向研究GJB2基因复合杂合突变致聋的机制，为耳聋的基因治疗提供新的角度和依据，具有重要的理论意义及潜在的临床应用价值。