The long term objective of this proposal is the identification of genes responsible for autosomal dominant congenital cataracts, a leading cause of blindness in children. Because of the limitations of studying this ocular disorder in humans, we propose to first devote our attention to mice in order to localize and characterize the candidate genes involved in cataractogenesis. Once identified, the mouse cataract genes can then be utilized to isolate the homologous human genes by hybridizing the mouse genes against a human lens cDNA library. Once the homologous human genes have been characterized, their normal structure i.e., DNA sequence, can be compared to the gene structured in individuals with autosomal dominant cataracts. A candidate gene harboring a mutation in a cataract patient would indicate that this abnormal gene is responsible for the cataract. Gene therapy could then be evaluated in the homologous mouse model which we originally studied for the purpose of preventing cataract formation during the embryonic period. As a starting point for these long term objectives, we propose to focus our studies on 5 independently segregating mutations causing autosomal dominant congenital cataracts in mice. First, we plan to map each abnormal gene to its respective chromosome by microsatellite markers. Second, we will investigate the histopathology of each cataract mutation on the developing lens. Finally, to identify additional independently segregating cataract mutations in mice we will conduct extensive allelism testing of 8 new cataract mutations.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010321-04
Application #
2019895
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1994-01-01
Project End
1997-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Favor, Jack; Bradley, Alan; Conte, Nathalie et al. (2009) Analysis of Pax6 contiguous gene deletions in the mouse, Mus musculus, identifies regions distinct from Pax6 responsible for extreme small-eye and belly-spotting phenotypes. Genetics 182:1077-88
Favor, Jack; Gloeckner, Christian Johannes; Neuhauser-Klaus, Angelika et al. (2008) Relationship of Pax6 activity levels to the extent of eye development in the mouse, Mus musculus. Genetics 179:1345-55
Favor, Jack; Gloeckner, Christian Johannes; Janik, Dirk et al. (2007) Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of Genetics 175:725-36
Huang, Kristen M; Geunes-Boyer, Scarlett; Wu, Sufen et al. (2004) Organization and annotation of the Xcat critical region: elimination of seven positional candidate genes. Genomics 83:893-901
Yu, Jindan; Farjo, Rafal; MacNee, Sean P et al. (2003) Annotation and analysis of 10,000 expressed sequence tags from developing mouse eye and adult retina. Genome Biol 4:R65
Brooks, David G; Manova-Todorova, Katia; Farmer, Jennifer et al. (2002) Ferritin crystal cataracts in hereditary hyperferritinemia cataract syndrome. Invest Ophthalmol Vis Sci 43:1121-6
Favor, J; Peters, H; Hermann, T et al. (2001) Molecular characterization of Pax6(2Neu) through Pax6(10Neu): an extension of the Pax6 allelic series and the identification of two possible hypomorph alleles in the mouse Mus musculus. Genetics 159:1689-700
Sidjanin, D J; Parker-Wilson, D M; Neuhauser-Klaus, A et al. (2001) A 76-bp deletion in the Mip gene causes autosomal dominant cataract in Hfi mice. Genomics 74:313-9
Favor, J; Neuhauser-Klaus, A (2000) Saturation mutagenesis for dominant eye morphological defects in the mouse Mus musculus. Mamm Genome 11:520-5
Grimes, P A; Koeberlein, B; Favor, J et al. (1998) Abnormal eye development associated with Cat4a, a dominant mouse cataract mutation on chromosome 8. Invest Ophthalmol Vis Sci 39:1863-9

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