家族性高胆固醇血症相关功能突变的组学筛查及基因敲除小鼠模型的建立

Familial hypercholesterolaemia (FH) is a human inherited disorder characterized by raised serum total cholesterol (TC) and LDL cholesterol levels. The high LDL cholesterol level results in accelerated atherosclerosis and increased risk of premature coronary heart disease. FH is a heterogeneous autosomal dominant (or recessive) disease. To date, although much of loss-of-function mutations from over 7 genes have been identified in partial FH patients, the large genetic heterogeneity of FH requires genome-wide scanning for the new candidates. Also, the mechanism by which pathogenic mutations in most candidate genes cause hypercholesterolaemia is not yet fully understood. Recently, the rapid development of high-throughput genomic technologies provides new opportunities for genetics study in medicine. In this study, we will be focused on detecting the new pathogenic mutations in novel FH families by exome-sequencing. A comprehensive genetic map of these mutations will be reconstructed using target-enrichment sequencing. Most import, the corresponding gene knock-out mice will illuminate the precise mechanism of the loss-of-function mutations in FH families. The completion of this project will further clarify the pathogenesis of FH, which will contribute to the understanding of the lipid metabolism disorders and guiding clinical practice.

家族性高胆固醇血症(Familial hypereholesterlolemia, FH)是一种以血浆总胆固醇和低密度脂蛋白胆固醇明显增高为特征的常见遗传性疾病，是引起动脉粥样硬化和早发冠心病的最重要危险因素。研究表明：FH是一种高遗传异质性的疾病，已知7种常见致病基因的功能性突变仅在部分患者中发现，多数家系的致病分子机制不明。近年来基于高胆固醇血症家系的连锁分析和散发患者的全基因组关联研究极大扩展了高胆固醇血症的候选致病基因谱，但尚缺乏相应的致病突变发现和分子机制研究。本项目基于已收集的高胆固醇血症遗传资源，通过外显子组测序系统发现FH家系的致病突变；并进行目标基因重测序描绘突变在家系或散发群体中的遗传模式；进一步建立相应的基因敲除小鼠模型，探讨突变致高胆固醇血症的分子机制。本项目的完成将为FH的诊断和治疗提供新的线索，为冠心病的研究提供新的思路。

家族性高胆固醇血症(Familial hypereholesterlolemia, FH)是一种高遗传异质性的疾病，已知4种常见致病基因的功能性突变仅在部分患者中发现，且多数家系的致病分子机制不明。本项目基于南昌人群建立大型胆固醇代谢紊乱遗传资源库，通过全基因组测序筛查到非经典FH家系的新致病突变（ABCG5 IVS8+2T>G和R466Q）；利用目标基因重测序描绘新突变在FH家系及散发胆固醇代谢紊乱群体中的遗传模式；并采用肝细胞模型探讨了突变 IVS8+2T>G 致病的全新分子机制；进一步采用CRISPR-Cas9技术建立基因敲除大鼠模型，探讨ABCG5/8复合体致隐性FH的分子机制。最终，本项目基于转化医学的策略对携带该突变的患者进行了精准医疗。本项目的完成为非经典FH 的诊断和治疗提供新的线索，为冠心病的研究提供了新的思路。