Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Nitabach, Michael

Abstract

Congenital Heart Disease (CHD) is the most common congenital malformation and a leading cause of infant mortality. While advances in genomic sequencing technology have enabled a fast and inexpensive candidate gene identification, the molecular mechanisms of CHD remain mostly unknown. Both nup107 and cacna1g are novel CHD genes identified in CHD patients with no plausible mechanisms explaining their roles in cardiac development. Here, we show that nup107 plays a key role in early embryonic patterning and subsequent organ development. The loss of Nup107 has a direct impact on germ layer specification, Left-Right patterning and downstream cardiac looping. Specifically, Nup107 depletion affects multiple developmental events by regulating the key step during the maternal-zygotic transition. In particular, Nup107 enhances the nuclear retention of miR427 primary transcript (pri-miR427), where it can be processed by Drosha to facilitate the clearance of maternal transcripts. While cacna1g mutations were also found in patients with CHD, we show that Cacna1g affects organogenesis via a completely distinct mechanism. Specifically, our results indicate that cacna1g loss-of-function affects Left-Right patterning and subsequent cardiac development by reducing the number of cilia in the Left-Right Organizer. In summary, we describe two mechanisms of how novel candidate genes affect different stages of embryonic development and contribute to CHD.

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