Genetic Regulation of Complex Neurological Disease

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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.