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Genetic and Developmental Studies of EVC and LBN

Lipscomb Sund, Kristen
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250274751

Abstract Details

2009, PhD, University of Cincinnati, Medicine : Molecular and Developmental Biology.
Atrioventricular septal defects (AVSDs) are clinically significant congenital cardiac defects that result from abnormal valvuloseptal development. In the absence of cardiac surgery, AVSDs result in congestive heart failure and death. To develop a better understanding of this heart malformation, we studied the role of two non-homologous head-to-head genes, EVC and LBN, in atrioventricular septal formation. Human mutations in EVC or LBN result in clinical features of Ellis van Creveld syndrome including AVSDs, disproportionate limb dwarfism, and post-axial polydactyly. In this dissertation, we applied genetic, developmental, and biochemical methods to study the role of EVC and LBN in normal development and disease pathogenesis. Mutational analysis of patient cohort with AVSD due to Ellis van Creveld syndrome led to the identification of novel mutations in EVC and LBN. Based on the human cardiac phenotype, we explored the presence of evc and lbn gene products in mouse during heart development. The gene products were co-expressed in atrioventricular (AV) septal structures, but the strongest expression was identified in the outflow tract, a tissue derived from the secondary heart field (SHF). EVC and LBN expression overlaps with Isl-1 in the dorsal mesenchymal protrusion, a SHF tissue that is crucial for AV septation. Analysis of endogenous protein in cell culture revealed co-expression of EVC and LBN with markers of primary cilia. The overlapping expression of mRNA and protein products and indistinguishable phenotypes resulting from mutation of either EVC or LBN suggests co-dependent function for these gene products in heart development. However, our biochemical studies show that this coordinate function is not a result of a transcriptional hierarchy. Based on locus heterogeneity of human mutations predicted to result in complete loss of either EVC or LBN protein function, the conserved bidirectional genomic organization of EVC and LBN, and overlapping expression of the gene products, we speculate that these proteins function coordinately during cardiac valvuloseptal development and that loss of this coordinate function results in AVSD as part of the Ellis van Creveld syndrome phenotype.
D. Woodrow Benson (Committee Chair)
Jeff Molkentin, Ph.D. (Committee Member)
Stephanie Ware, M.D., Ph.D. (Committee Member)
Nancy Warren, M.S., CGC (Committee Member)
Katherine Yutzey, Ph.D. (Committee Member)
138 p.
Genetics
Ellis van Creveld syndrome; AVSD; cilia; DMP; EVC; LBN

Recommended Citations

Citations

  • Lipscomb Sund, K. (2009). Genetic and Developmental Studies of EVC and LBN [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250274751

    APA Style (7th edition)

  • Lipscomb Sund, Kristen. Genetic and Developmental Studies of EVC and LBN. 2009. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250274751.

    MLA Style (8th edition)

  • Lipscomb Sund, Kristen. "Genetic and Developmental Studies of EVC and LBN." Doctoral dissertation, University of Cincinnati, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250274751

    Chicago Manual of Style (17th edition)

ucin1250274751
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© 2009, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.