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)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Genetics of Health and Disease Study Section (GHD)
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Coulombe, James N
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Brigham and Women'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
Stottmann, R W; Donlin, M; Hafner, A et al. (2013) A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse. Hum Mol Genet 22:4053-63
Stottmann, Rolf W; Turbe-Doan, Annick; Tran, Pamela et al. (2011) Cholesterol metabolism is required for intracellular hedgehog signal transduction in vivo. PLoS Genet 7:e1002224
Zheng, Yuxiang; Yin, Huiyong; Boeglin, William E et al. (2011) Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelope. J Biol Chem 286:24046-56
Dwyer, Noelle D; Manning, Danielle K; Moran, Jennifer L et al. (2011) A forward genetic screen with a thalamocortical axon reporter mouse yields novel neurodevelopment mutants and a distinct emx2 mutant phenotype. Neural Dev 6:3
Stottmann, R W; Bjork, B C; Doyle, J B et al. (2010) Identification of a Van der Woude syndrome mutation in the cleft palate 1 mutant mouse. Genesis 48:303-8
Kamp, Anna; Peterson, Michael A; Svenson, Karen L et al. (2010) Genome-wide identification of mouse congenital heart disease loci. Hum Mol Genet 19:3105-13
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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