In EPP, Mutations in ClpX Gene Lead to Dysfunctional Heme Production

The ClpX protein recently has been studied for its role in causing erythropoietic protoporphyria (EPP). In a review study, researchers explored this connection and recommended further genetic studies.

The study, “The role of ClpX in erythropoietic protoporphyria,” was published in the journal Hematology, Transfusion and Cell Therapy.

EPP, the most common cutaneous porphyria in children, is caused by the accumulation of protoporphyrin, a photosensitive organic molecule that binds to iron to form the heme molecule. Heme is essential in enabling blood cells to carry oxygen and in breaking down chemical compounds in the liver.

Accumulated protoporphyrin reacts with sunlight, resulting in the production of damaging reactive oxygen species that can lead to cellular damage and death. This causes extreme sensitivity to sunlight and can ultimately lead to liver damage.

This build-up of protoporphyrin is known to be a result of mutations in genes involved in the heme production pathway, such as FECH and ALAS2.

Mutations in the FECH gene, leading to a non-functional FECH enzyme, account for approximately 90% of EPP cases; mutations in the ALAS2 gene are responsible for 5% of cases.

“Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis,” the researchers stated.

A recent report of a family with history of EPP but no mutations in FECH or ALAS2 revealed a mutation in the ClpX gene in all affected family members. ClpX provides the instructions to produce the ClpX enzyme, involved in the structural remodeling of proteins — ultimately changing their biological activity — and in the degradation of those proteins through interaction with another enzyme called ClpP.

The mutation was later found to lead to increased activity of ALAS2, along with higher levels of protoporphyrin, suggesting that the ClpX enzyme was involved in the activation and degradation of ALAS2. The disruption of that balance leads to EPP.

The mutated ClpX was still capable of activating ALAS2, but it was unable to send ALAS2 to be degraded by ClpP.

The authors noted that additional studies are needed not only to determine the interactions between the mutated forms of ALAS2 and ClpX, but also the prevalence of ClpX mutations in patients with EPP.

Also, while mutations in the ClpP gene could potentially be another cause of EPP, the effects of such mutations remain unexplored, and “the potential role of ClpP in EPP and heme biosynthesis [production] remains an exciting avenue of future research,” the researchers said.

They also noted the limited treatment options available for EPP patients and the lack of an efficient treatment plan, but highlighted that increasing the activity of FECH in patients with FECH mutations or increasing iron uptake through small molecules that act as iron carriers could potentially reduce protoporphyrin levels and the associated damage.

Additional studies are needed to clarify the potential therapeutic benefits of these strategies, as well as to develop new therapies.