AIFM1及VARS2基因及其新突变对线粒体功能的影响

线粒体病是一组严重的能量代谢性疾病，可导致脑、心、肌肉、肝肾等多脏器损害，遗传方式复杂，约25%的患者因线粒体基因突变导致，75%为核基因突变引发。迄今已知1500余种基因与线粒体结构、代谢及运输等相关。前期研究中，采用二代基因测序进行线粒体病相关核基因分析，我们发现了36例线粒体病患者存在不同类型的核基因突变，9例为非常罕见基因的变异，其中VARS2突变的患者为国际首例，2例AIFM1新突变的Leigh综合征患者为全球第6、7例。本课题将以患者细胞为模型，分析线粒体转录翻译效率、线粒体复合物稳定性及线粒体代偿功能，运用线粒体功能分析、基因过表达、RNA干扰等技术对新鉴定的VARS2和 AIFM1基因及4种新突变进行研究，进一步解释VARS2和 AIFM1基因的功能，以VARS2基因为重，探讨4种新突变在线粒体病发生发展中的机制，为线粒体病的遗传咨询和产前诊断研究提供科学参考。

Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy resulting in brain, heart, muscle, liver, kidney or multi-organ damage. Mitochondrial disorders may be caused by mutations in mitochondrial DNA (25%) or in nuclear genes (75%) and inherited as varied hereditary modes. Most mitochondrial function and biogenesis are controlled by nuclear DNA. Most of the estimated 1,500 mitochondrial proteins and components targeted to mitochondria are nuclear-encoded. Defects in nuclear-encoded mitochondrial genes are associated with mitochondrial structure, metabolism and transportation. Recently, next-generation DNA sequencing leads to great success in uncovering new disease-causing genes. In our preliminary study, practicing next-generation sequencing, nuclear gene defects have been found in 36 patients with severe mitochondrial disorders. 9 cases have mutations on very rare genes. Two mutations on VARS2 were the very first ones discovered around the world. The patients with two novel mutations on AIFM1 gene were the 6th and 7th patients in the world, respectively. With regard to finding mitochondrial transcription and translation level, the stability of mitochondrial respiratory chain complex, and mitochondrial compensatory function change, we are planning to perform functional studies as mitochondrial function analysis, gene over expression, RNA interference on fibroblasts or lymphocytes of 3 patients. The project might contribute to deepening the understanding of the function of VARS2 and AIFM1 genes associate with mitochondrial diseases and be helpful for the etiologic investigation, genetic counseling and prenatal diagnosis of nuclear gene-related mitochondrial disease.