Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Mustafa Khoka

Abstract

Recent advances in genetic sequencing technologies have enabled identification of numerous congenital heart disease (CHD) candidate genes. One such gene, endoplasmic reticulum transmembrane complex 1 (EMC1), has been implicated in proper transmembrane protein topogenesis and associated with varied patient phenotypes. Using a western clawed frog (Xenopus tropicalis—X. tropicalis) animal model, we recapitulate a cardiac phenotype with EMC1 loss of function and identify additional pigment and craniofacial phenotypes consistent with a neural crest cell (NCC) pathology, which we corroborate at the molecular level. We subsequently demonstrate that EMC1 loss of function causes abnormal WNT signaling, as manifested in abnormal β-Catenin levels and localization, and establish a plausible mechanism for abnormal NCC development in which EMC1 loss of function affects the transmembrane WNT signal transducers FZD2 and FZD7. We additionally show that EMC1 loss of function affects expression and/or localization of the transmembrane proteins rhodopsin and the nicotinic acetylcholine receptor (nAChR) and confirm that EMC1 loss of function triggers an un-folded protein response, likely mediated by accumulation of mis-localized transmembrane proteins. Altogether, our work demonstrates a complex and yet elegantly plausible model for CHD pathogenesis in patients with EMC1 mutations, including the unexpected twist of NCC pathology and a unifying theory for other patient phenotypes.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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