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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01MH071801-05
Application #
7385956
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Desmond, Nancy L
Project Start
2005-04-19
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$133,837
Indirect Cost
Name
Rensselaer Polytechnic Institute
Department
Type
DUNS #
002430742
City
Troy
State
NY
Country
United States
Zip Code
12180
Tuz, Karina; Hsiao, Yi-Chun; Juárez, Oscar et al. (2013) The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions. J Biol Chem 288:13676-94
Hsiao, Yi-Chun; Tuz, Karina; Ferland, Russell J (2012) Trafficking in and to the primary cilium. Cilia 1:4
Zhang, Jingping; Neal, Jason; Lian, Gewei et al. (2012) Brefeldin A-inhibited guanine exchange factor 2 regulates filamin A phosphorylation and neuronal migration. J Neurosci 32:12619-29
Westfall, Jennifer E; Hoyt, Carlton; Liu, Qin et al. (2010) Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1. J Neurosci 30:8759-68
Hsiao, Yi-Chun; Tong, Zachary J; Westfall, Jennifer E et al. (2009) Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking. Hum Mol Genet 18:3926-41
Ferland, Russell J; Guerrini, Renzo (2009) Nodular heterotopia is built upon layers. Neurology 73:742-3
Ferland, Russell J; Batiz, Luis Federico; Neal, Jason et al. (2009) Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia. Hum Mol Genet 18:497-516
Papandrea, Dominick; Kukol, Whitney S; Anderson, Tara M et al. (2009) Analysis of flurothyl-induced myoclonus in inbred strains of mice. Epilepsy Res 87:130-6
Yu, Fuli; Keinan, Alon; Chen, Hua et al. (2009) Detecting natural selection by empirical comparison to random regions of the genome. Hum Mol Genet 18:4853-67
Papandrea, Dominick; Anderson, Tara M; Herron, Bruce J et al. (2009) Dissociation of seizure traits in inbred strains of mice using the flurothyl kindling model of epileptogenesis. Exp Neurol 215:60-8

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