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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD036404-11
Application #
7986279
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Coulombe, James N
Project Start
1998-04-01
Project End
2015-05-31
Budget Start
2010-09-14
Budget End
2011-05-31
Support Year
11
Fiscal Year
2010
Total Cost
$436,166
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Geister, Krista A; Timms, Andrew E; Beier, David R (2018) Optimizing Genomic Methods for Mapping and Identification of Candidate Variants in ENU Mutagenesis Screens Using Inbred Mice. G3 (Bethesda) 8:401-409
Abdelhamed, Zakia; Vuong, Shawn M; Hill, Lauren et al. (2018) A mutation in Ccdc39 causes neonatal hydrocephalus with abnormal motile cilia development in mice. Development 145:
Strassman, Alexander; Schnütgen, Frank; Dai, Qi et al. (2017) Generation of a multipurpose Prdm16 mouse allele by targeted gene trapping. Dis Model Mech 10:909-922
Ha, Seungshin; Tripathi, Prem P; Mihalas, Anca B et al. (2017) C-Terminal Region Truncation of RELN Disrupts an Interaction with VLDLR, Causing Abnormal Development of the Cerebral Cortex and Hippocampus. J Neurosci 37:960-971
Ha, Seungshin; Lindsay, Anna M; Timms, Andrew E et al. (2016) Mutations in Dnaaf1 and Lrrc48 Cause Hydrocephalus, Laterality Defects, and Sinusitis in Mice. G3 (Bethesda) 6:2479-87
Gallego-Llamas, Jabier; Timms, Andrew E; Pitstick, Rose et al. (2016) Improvement of ENU Mutagenesis Efficiency Using Serial Injection and Mismatch Repair Deficiency Mice. PLoS One 11:e0159377
Jacobs, Damon T; Silva, Luciane M; Allard, Bailey A et al. (2016) Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome. Dis Model Mech 9:789-98
Gallego-Llamas, Jabier; Timms, Andrew E; Geister, Krista A et al. (2015) Variant mapping and mutation discovery in inbred mice using next-generation sequencing. BMC Genomics 16:913
Ha, Seungshin; Stottmann, Rolf W; Furley, Andrew J et al. (2015) A forward genetic screen in mice identifies mutants with abnormal cortical patterning. Cereb Cortex 25:167-79
Czarnecki, Peter G; Gabriel, George C; Manning, Danielle K et al. (2015) ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning. Nat Commun 6:6023

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