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Degree

Doctor of Philosophy, Case Western Reserve University, Genetics, 2008.

Abstract

More than 4,500 different congenital defects have been identified. Together they are the leading cause of infant death in the United States. Many defects may be attributed to Mendelian inheritance of genetic variants, teratogenic exposure, chromosomal abnormalities and maternal infections. However, sixty percent of congenital defects have no identifiable cause. To investigate a genetic component of sporadic birth defects, we used the Disorganization (Ds) inbred strain. Disorganization is a spontaneous mutation in mice with the ability to cause an unprecedented variety of sporadic birth defects affecting most morphologic features. Defects include syndactylies and polydactylies, mirror-image limb duplications, supernumerary limbs, cleft tongue, fused kidney, rachischisis, thoracoschisis and gastroschisis, and various hamartomas. Disorganization is a dominant, gain-of-function mutation. Positional cloning enabled us to reduce the Disorganization critical region from an interval of 913,263 bp to 367,303 bp. Genomic BACs spanning this interval were sequenced and 246 polymorphisms between Ds and C57BL/6J were discovered. A unique ETn retrotransposon was found. A Disorganization BAC spanning the region containing this retrotransposon was used to generate transgenic mice resulting in an affected founder. This founder produced an affected F2 progeny. Collectively, these studies lend support to a role of the ETn retrotransposon in the Disorganization phenotype. The pathways that Disorganization disrupts during development remain to be identified. The ETn retrotransposon did not insert into any known genes, promoters or enhancers. The gene Gata4, two RIKEN sequences and the last three exons of Blk are present on the BAC used to create the transgenic founder. A model of Disorganization is proposed in which the ETn retrotransposon causes ectopic expression of the Gata4 gene. These studies and future studies arising from this work will help illuminate factors involved in normal development, define epigenetic contributions to sporadic birth defects, and possibly lead to novel therapies for those at risk for birth defects.

Subject Headings

Biology, Genetics

Keywords

birth defects

Advisor

Joseph Nadeau

Document number: case1189146887
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=case1189146887

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