Genetic modifiers of phosphoinositide mediated neurodegeneration

描述(申请人提供)：我们正在研究由于信号脂PI(3，5)P2(磷脂酰肌醇-3，5-二磷酸)缺乏而引起的神经疾病。PI(3，5)P2定位于内切酶系统的膜上。PI(3，5)P2是由一个包含PIKfyve激酶、支架蛋白VAC14和磷酸酶FIG4的复合体产生的(金等，2008)。我们证明FIG4的突变导致人类神经疾病Charcot-Marie-Tooth 4J型(CMT4J)、尤尼斯-瓦隆综合征和多小脑回(Chow等人，2007年；Campeau等人，2013年；Baulac等人，2014)。患有CMT4J和多微脑回的患者从儿童早期到成年表现出疾病严重程度的差异性(Nicholson等人，2011年；Ben Cheikh BO等人，2009年)。在不同品系背景的小鼠模型中模拟不同的严重程度。Fig4基因缺失和Vac14基因L156R纯合子小鼠在C57BL/6J品系上表现出早期致死性，但在C3HeB/FEJ品系上存活时间延长。我们独特的PI(3，5)P2缺乏症小鼠模型将被用来研究这种差异，使用连锁和QTL分析来阐明生存性状的遗传结构，以确定影响图4和Vac14突变体生存的共同修饰物。未来的工作将确定治疗人类疾病的负责基因和靶向途径。

DESCRIPTION (provided by applicant): We are studying neurological disorders caused by deficiency of the signaling lipid PI(3,5)P2 (phosphatidylinositol-3,5-bisphosphate). PI(3,5)P2 is localized on membranes of the endolysosomal system. PI(3,5)P2 is generated by a complex including the kinase PIKFYVE, the scaffold protein VAC14, and the phosphatase FIG4 (Jin et al 2008). We demonstrated that mutations of FIG4 are responsible for the human neurological disorders Charcot-Marie-Tooth type 4J (CMT4J), Yunis-Varon syndrome, and polymicrogyria (Chow et al., 2007; Campeau et al., 2013; Baulac et al., 2014). Individuals with CMT4J and polymicrogyria exhibit variability in disease severity from early childhood to adulthood (Nicholson et al., 2011; Ben Cheikh BO et al., 2009). Variable severity is mimicked in mouse models with different strain backgrounds. Mice null for Fig4 and those homozygous for the Vac14 substitution L156R display early lethality on strain C57BL/6J but extended survival on strain C3HeB/FeJ. Our unique collection of mouse models of PI(3,5)P2 deficiency will be used to investigate this difference, using linkage and QTL analysis to elucidate the genetic architecture of the survival trait, to identify shared modifiers affecting survival of both Fig4 an Vac14 mutants. Future work will identify the responsible genes and target pathways for treatment of the human disorders.