A recent study by Granata et al. (2022) on gene expression in blood cells from a cohort of patients suffering from ferrochelatase-deficient erythropoietic protoporphyria (EPP) confirms earlier findings of the involvement of a misguided compensatory mechanism to produce more hemoglobin for the disease manifestation. By using a new, extremely sensitive method to quantify the messenger RNA count in the blood of patients and healthy controls called “digital PCR”, the group was able to measure how actively the genes of the heme biosynthetic pathway are used by the cells. In EPP, the last step of the heme biosynthesis is affected by mutations that lead to a lower amount of the enzyme “ferrochelatase” which combines iron with a substance called “protoporphyrin” to form the red blood dye heme. Heme is essential for binding and distributing the oxygen in the blood and tissues.
Overly active ALAS2
EPP has long been seen as a disorder in which the phototoxic molecule protoporphyrin accumulates because of insufficient amounts of ferrochelatase. However, earlier findings demonstrated in addition an unexpected increase of the first enzyme of the pathway – aminolevulinic acid synthase 2 (ALAS2). In people with a normal activity of all heme genes, the underlying mechanism to increase ALAS2 in case of a heme deficiency could help, for example, to compensate for a blood loss. However, in EPP, an overly active ALAS2 contributes to the amount of protoporphyrin produced by the cells and therefore to the disease severity.
New therapeutic target
The findings of Granata and colleagues therefore strengthen the evidence base for this modifying factor of EPP. Moreover, the increase in ALAS2 constitutes a new therapeutic target to causatively treat EPP. Substances that might influence the activity of ALAS2 like Bitopertin and related compounds are already in the pre-clinical stage. Furthermore, hitherto unknown alterations in the gene expressions of additional heme biosynthetic genes and new association with parameters of the iron metabolism are described for EPP in the article for the first time.