Date of Award

January 2020

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Mustafa Khokha


Congenital heart disease (CHD) is the most common major birth defect in children, affecting nearly 3% of children and is the leading cause of infant mortality. Heterotaxy (Htx) is a disorder of left-right (LR) patterning, in which organs, including the heart, are mispatterned relative to the LR axis. Htx is associated with severe forms of CHD, but its genetic causes remain largely undefined. Exome sequencing studies of large patient cohorts have recently revealed hundreds of CHD/Htx candidate disease genes, which now need to be validated in experimental systems for causality in order to better understand the causes and biological mechanisms of CHD/Htx. Recently, the membrane-bound transcription factor MYRF has emerged as a candidate CHD/Htx gene in 14 patients with 13 unique variants. This is intriguing, as MYRF has an established role in the generation and maintenance of myelin in the central nervous system, but no known functional role in LR patterning or cardiac development. Here, we show that myrf is essential for LR patterning and gastrulation in Xenopus. Our data suggests both the LR patterning and delayed gastrulation phenotype are due to an upregulation of Nodal signaling indicating that myrf normally suppresses nodal. Searching for candidate genes downstream of MYRF, we identified the proprotein convertase FURIN as a potential target. Our results demonstrate that myrf suppresses furin transcription, which affects Nodal signaling via furin’s role in nodal ligand processing. Together, we provide a plausible mechanism for LR patterning defects and congenital heart disease in patients with MYRF variants. In doing so, we hope to better elucidate the molecular mechanisms of cardiac development and LR patterning and understand how these variants lead to disease in order to eventually provide genetic counseling, prognosis and therapeutics for patients with this rare disease.


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