Developmental malformations of the brain are collectively recognized as an increasingly important cause of mental retardation, epilepsy, and perhaps autism. These disorders have deleterious effects on both the psychological and physical well-being of the affected individual. However, identification of causative genes and elucidation of their functions in the context of these developmental brain abnormalities provide valuable insights into human brain development. Joubert syndrome (JS) is an autosomal recessive developmental brain condition, which is characterized anatomically by cerebellar and brainstem malformations, and clinically by hypotonia, breathing abnormalities, atypical eye movements, cognitive problems, and autistic features. The goals of this proposal are to identify one of the causative genes for JS and to study the function of this gene in brain development. Our preliminary work mapped a JS locus to chromosome 6q. Our further studies identified a causative gene for JS, which is a novel gene encoding a putative adaptor protein called AHI1.
Specific Aim 1 will test the hypothesis that AHI1 is a causative gene for JS by further analyzing the genetic and clinical aspects of JS in our patients, performing mutational analyses of AHI1 in our JS families, and analyzing the genomic structure of AHI1.
Specific Aim 2 will characterize the temporal and spatial expression of AHI1 at both the mRNA and protein levels in addition to generating and characterizing mice with a targeted deletion of Ahi1.
Specific Aim 3 will identify proteins that interact with AHI1 by yeast two-hybrid and confirm these interactions by co-immunoprecipitation analyses. The applicant has a PhD. He earned his doctoral degree in Neuroscience studying the role of the perirhinal cortex, the ventromedial nucleus of the hypothalamus, and hippocampal neurogenesis in animal models of epilepsy. His mentor is Christopher A. Walsh, MD, PhD, whose research interests center on genetic approaches toward understanding basic mechanisms governing the development of the brain. This research proposal focuses on training the candidate in methods of 1) genetic mapping, linkage analysis, and genetic analyses, and 2) neurogenetics and molecular biological approaches to brain development. It is the candidate's intention to combine both his previous training in neuroanatomy and behavior with these new molecular and genetic approaches in order to pursue an academic career in Neuroscience.
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