Leber遗传性视神经病变（LHON）是典型的母系遗传疾病。三个线粒体原发性突变是其发病的主要分子基础，但它表型的复杂性提示核基因参与LHON致病。尤其是LHON男性多发，预测X染色体上有调控LHON的核基因，但具体基因未见报导。我们已通过遗传家系的全外显子测序与分析，发现PRICKLE3基因与LHON致病相关。本项目拟在此研究基础上，以细胞和小鼠模型为材料，诠释PRICKLE3在LHON致病中的机制：1) 揭示PRICKLE3突变对细胞线粒体形态与功能的影响； 2) 探究PRICKLE3调控线粒体功能的分子机制；3)阐明Prickle3在小鼠视神经节细胞和视网膜中的作用机制。本项目的实施不仅有助于诠释LHON致病机制，丰富核基因与线粒体基因的互作机理，也将为临床转化提供科学依据。

Leber’s hereditary optic neurophthy (LHON) is a maternally inherited eye disease. Three most common mutations are accounted for 90% LHON cases in some country and 50% in China. Since LHON is notable for its incomplete penetrance and man bias, an agreement that X-chromosomal gene (located on the area Xp21.1-q21.2 or Xq25-27.2) affecting the phenotypic expression was postulated in several studies and failed to be identified to date. On the basis of our recent study in a LHON pedigree by the whole-exome sequencing, we found an X-linked gene PRICKLE3 on Xp11.23 with homozygous missense mutation in a Mendel fashion. Here, we would set out to prove that PRICKLE3 is a novel gene conferred the risk of LHON by experiments in vivo and in vitro: 1) the role of PRICKLE3 in mitochondrial morphology and function; 2) the molecular mechanism of PRICKLE3 to aggravate the mitochondrial dysfunction; 3) The function of Prickle3 in RGCs and retinas from the wild-type and Prickle3-/- or Prickle3 (157C>T) mice. This study may not only provide new insights into the pathogenesis of LHON but also inspire us to well understand the complex phenotype of LHON attributed to the interaction of genes between nucleus and mitochondria, which in turn paving the way for future basic research and therapeutic interventions.