Genetic Regulation of Complex Neurological Disease

描述(申请人提供)：许多因素使基因复杂的疾病变得复杂。传统上，它们被定义为多种遗传变异和非遗传因素之间的相互作用。基因组测序和种内变异的最新进展引起了人们对在人类和模式生物中识别多基因变异的极大兴趣，并取得了一些成功。但人们不能忽视生理复杂性的重要性，即使是在与复杂的生物系统相互作用时可能造成严重破坏的单个变种也是如此。这一概念在某些领域得到了很好的理解--例如发育、退化--但对于某些功能表型，如中枢神经系统的兴奋性障碍，它的研究还不够深入。可以肯定的是，癫痫在基因上是复杂的，但作为大脑的典型兴奋性障碍，它也是探讨其他更少了解的功能性障碍的典范，如精神分裂症和其他精神障碍，这些疾病可能也有兴奋病理。神经元的兴奋性主要由离子通道和转运体、神经递质受体和突触蛋白等分子决定，这些分子控制膜电位和突触信号，以实现兴奋和抑制的平衡，从而实现适当的高级大脑功能。尽管编码这些分子的基因中的顺式变异可以导致特定的表型，但调节它们表达的反式因子必须是维持这种平衡在更高水平上的关键，甚至可能是协调的。最近在小鼠身上发现了一个严重的亚型突变，在编码Brunol4的基因中，Brunol4是Bruno/CUGBP/CELF RNA结合蛋白家族中一个大脑特异的、富含海马体的成员。Brunol4突变体有复杂的癫痫发作障碍，这取决于Brunol4基因和遗传背景，也可能有行为表型。基因表达谱显示，海马区表达的基因在突变体中下调，其中几个已在mRNA和蛋白质水平上得到证实。虽然已知这些分子在突触功能中具有密切的作用，例如当基因被敲除时，对Brunol4突变小鼠的临床和遗传学评估表明，正是几个基因的协调失调同时导致了复杂的癫痫发作障碍。这项研究计划目前的目标是了解Brunol4是如何通过以突变和转基因小鼠为中心的各种方法来协调调节其目标转录物在大脑中的表达的方式。该系统为理解复杂神经疾病的结构提供了一种新的模型，受多基因遗传的影响，但超出了多基因遗传的影响。

DESCRIPTION (provided by applicant): Many factors make genetically complex diseases complex. Classically they are defined as an interaction between multiple genetic variants and non-genetic factors. Recent progress in genome sequencing and intraspecies variation has generated much interest in identifying polygenic variants in human and in model organisms, with some success. But one cannot lose sight of the importance of physiological complexity, even from single variants which can wreak havoc when they interact with a complex biological system. This concept is well appreciated in some arenas - e.g. development, degeneration - but for certain functional phenotypes such as excitability disorders of the central nervous system, it is understudied. Epilepsy is genetically complex to be sure, but as the canonical excitability disorder of the brain, it also serves as a leading example for approaching other, more poorly understood functional disorders such as schizophrenia and other psychiatric disorders which are likely to have excito-pathology as well. Neuronal excitability is determined primarily by molecules such as ion channels and transporters, neurotransmitter receptors, and synaptic proteins, which control membrane potential and synaptic signaling in order to achieve a balance of excitation and inhibition, thus enabling appropriate high-level brain function. Although cis-variants in genes encoding these molecules can lead to specific phenotypes, trans-factors that regulate their expression must be critical for maintaining this balance at a higher, perhaps even coordinated level. Recently a severely hypomorphic mutation was identified in mice, in the gene encoding Brunol4, a brain-specific, hippocampus-enriched member of the Bruno/CUGBP/CELF family of RNA binding proteins. Brunol4 mutants have a complex seizure disorder, depending upon Brunol4 genotype and genetic background, and may have behavioral phenotypes as well. Gene expression profiling revealed an enrichment of hippocampally-expressed genes that are downregulated in mutants, several of which have been validated as such at the mRNA and protein level. Although these molecules are known to have proximate roles in synaptic function, for example when knocked-out, clinical and genetic assessment of Brunol4 mutant mice suggests that it is the coordinate dysregulation of several genes simultaneously that leads to the complex seizure disorder. The current goal of this research program is to understand the way in which Brunol4 coordinately regulates the expression of its target transcripts in the brain, by using a variety of approaches centering on studies in mutant and transgenic mice. The system provides a new kind of model, influenced by, but extending beyond polygenic inheritance, for understanding the architecture of complex neurological disease.