We have undertaken a project to generate models of human congenital defects by screening ENU-mutagenized mice for recessive mutations affecting late embryonic development. The screen incorporated a genetic mapping component, with an aim to facilitate the positional cloning and functional characterization of the mutant genes. The strategy has worked well, and we have generated many mutant lines with phenotypes similar to human malformation syndromes and birth defects. The spectrum of abnormalities found to date is remarkably varied; for example, we have generated models of spondylocostal dysostosis, Robin sequence, congenital diaphragmatic defect, non-syndromic cleft palate, polycystic kidney disease, epidermal bullosa, non-bullosa congenital icthyosiform erythroderma, and structural heart disease. We have mapped a number of these, and identified the mutated locus in 9 lines. To accomplish this, we have taken advantage of efficent technologies for genetic mapping and positional cloning. The functions for many of the genes we have identified are not well understood, and we have initated a variety of biochemical and developmental studies to explore them. In addition to characterizing the biology of the defects in the mutant mice, we have in several cases established that the genes we identified play a role in the causation of human disease. Thus, all of the premises that were the basis of our original proposal have been experimentally validated. In this continuation proposal we hope to refine the specificity and sensitivity of the screen and optimize several aspects of the analysis, while maintaining the fundamental approach that has thus far proven so productive.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD036404-08
Application #
7238009
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Coulombe, James N
Project Start
1998-04-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
8
Fiscal Year
2007
Total Cost
$298,062
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; SchnĆ¼tgen, 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
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
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
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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