The effects a novel mutation in the mitochondrial unfoldase protein ClpX and a ClpX deficiency have on the regulation of the erythroid heme biosynthesis pathway
Date
2025
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Publisher
University of Delaware
Abstract
Mutations in genes involved in the heme biosynthesis pathway can cause various hematologic disorders. Previous research determined that heme synthesis is regulated by the mitochondrial AAA+ unfoldase ClpX through the activation of ALAS which initiates the first step of the pathway. A reported dominant mutation in the ATPase active site of human ClpX, p. Gly298Asp, showed the phenotypical accumulation of the intermediate protoporphyrin IX of erythropoietic protoporphyria (EPP) and effects on ALAS in heme synthesis (Yien, 2017). We created a CRISPR knock in murine cell model to further investigate the effects of this CLPX G298D mutation on the mitochondrial steps of the pathway in addition to identifying how iron status can act as a possible therapeutic for the mutation’s clinical effects. In addition, previous work investigating the role of CLPX in heme synthesis via a Clpx-/- MEL cell line is expanded upon using a more primary, physiologically relevant cell line, G1E-ER4 cells, where we are seeing less severe phenotypical results that may lead to how this loss of Clpx will act in a mouse model (Rondelli, 2021).
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Keywords
Mutations, Genes, Erythropoietic protoporphyria, Murine cell model