The previous cycles of this grant have supported our efforts to generate models of human congenital defects by screening ENU-mutagenized mice for recessive mutations affecting late embryonic development. These screens incorporated a genetic mapping component to facilitate the positional cloning and functional characterization of the mutant genes. The strategy has worked well, and we have generated many mice with phenotypes similar to human malformation syndromes and birth defects. Our future effort has even greater potential productivity, as the overall task of mutation discovery continues to be facilitated by rapid progress in technologies for genomic analysis. In this continuation proposal we aim to optimize several aspects of the project, while maintaining the fundamental approach that has thus far proven so productive. Specifically, we propose strategies for rapid mutant validation and for more rapidly translating gene discovery into functional analysis.

Public Health Relevance

We are able to identify mutations causing abnormalities of organ development by systematically screening mice treated with the chemical mutagen ENU. The generation of powerful tools for genome analysis allows us to rapidly identify the gene mutated in these abnormal mice. This provides insight into the causes of congenital birth defects and the basic biology of human development.

National Institute of Health (NIH)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Coulombe, James N
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Seattle Children's Hospital
United States
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Tran, Pamela V; Talbott, George C; Turbe-Doan, Annick et al. (2014) Downregulating hedgehog signaling reduces renal cystogenic potential of mouse models. J Am Soc Nephrol 25:2201-12
Stottmann, Rolf; Beier, David (2014) ENU Mutagenesis in the Mouse. Curr Protoc Hum Genet 82:15.4.1-15.4.10
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Bjork, Bryan C; Turbe-Doan, Annick; Prysak, Mary et al. (2010) Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet 19:774-89
Smits, Patrick; Bolton, Andrew D; Funari, Vincent et al. (2010) Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210. N Engl J Med 362:206-16

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