Structural Brain Defects (SBDs) constitutes an immense health problem. Approximately 4-6% ofthe human population is affected by developmental disorders that affect the structure ofthe nervous system. A large number of SBD cases are or genetic origin. Despite major advances in human genetics and genome research, the majority of genes that are linked SBDs still need to be identified. There is also a pressing need for animal models to study gene function in the developing brain, to define the molecular pathogenesis of SBDs, and to develop therapeutic approaches for their treatment. Significantly, the brain of human and mice share many anatomical and molecular features, suggesting that the genetic program controlling CNS development is in large parts conserved between the two species. The mouse is also a leading research tool for genetic studies. We therefore hypothesize that we will generate by forward and reverse genetics in mice valuable animal models for studying the genetic program that controls brain development and for defining the molecular pathogenesis of inherited forms of SBDs in humans. This hypothesis is supported by our preliminary data, which show that we can generate mouse models for SBDs by forward and reverse genetics. Based on these findings, we therefore proposes two specific aims.
In Aim 1, we will capitalize on our expertise in forward genetics in mice using ENU as a mutagen, to generate mouse lines afflicted with inherited forms of SBDs, to positionally clone the affected genes, and to study gene function. The other participants of the program project grants will test the extent to which the genes that we identify are associated with SBDs in humans and zebrafish.
In Aim 2, we will use reverse genetics approaches to generate mouse lines carrying mutations associated with SBDs in humans or zebrafish that have been identified by the other participants of this program project proposal. We anticipate that we will identify a wide range of mutations that cause SBDs and generate important mouse models to study disease mechanisms.

Public Health Relevance

Structural brain defects (SBDs) are frequently of genetic origin and one ofthe most common forms of structural birth defects in humans. This proposal seeks to identify genes that are linked to SBDs and to develop mouse models for studying disease mechanisms. The animal models hold great promise as tools for the development of therapeutic approaches towards the treatment of SBDs.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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University of California San Diego
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Marin-Valencia, Isaac; Guerrini, Renzo; Gleeson, Joseph G (2014) Pathogenetic mechanisms of focal cortical dysplasia. Epilepsia 55:970-8
Schaffer, Ashleigh E; Eggens, Veerle R C; Caglayan, Ahmet Okay et al. (2014) CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell 157:651-63
Marín, Oscar; Müller, Ulrich (2014) Lineage origins of GABAergic versus glutamatergic neurons in the neocortex. Curr Opin Neurobiol 26:132-41
Novarino, Gaia; Fenstermaker, Ali G; Zaki, Maha S et al. (2014) Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343:506-11
Thomas, Sophie; Wright, Kevin J; Le Corre, Stéphanie et al. (2014) A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum Mutat 35:137-46
Kinsella, Marcus; Patel, Anand; Bafna, Vineet (2014) The elusive evidence for chromothripsis. Nucleic Acids Res 42:8231-42
Ronen, Roy; Zhou, Dan; Bafna, Vineet et al. (2014) The genetic basis of chronic mountain sickness. Physiology (Bethesda) 29:403-12
Kramer, Michael; Dutkowski, Janusz; Yu, Michael et al. (2014) Inferring gene ontologies from pairwise similarity data. Bioinformatics 30:i34-42
Akizu, Naiara; Silhavy, Jennifer L; Rosti, Rasim Ozgur et al. (2014) Mutations in CSPP1 lead to classical Joubert syndrome. Am J Hum Genet 94:80-6
Gil-Sanz, Cristina; Landeira, Bruna; Ramos, Cynthia et al. (2014) Proliferative defects and formation of a double cortex in mice lacking Mltt4 and Cdh2 in the dorsal telencephalon. J Neurosci 34:10475-87

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