In less enlightened times, anyone with a pale appearance, nocturnal habits, and a habit of drinking animal blood—should blood transfusions have been unavailable—may have been accused of being a vampire. We now know, however, that these attributes aren’t necessarily signs of the undead. Instead, they may point to a medical condition, to one of several porphyrias, the most common of which is called erythropoietic protoporphyria (EPP).

Porphyrias have been linked to several genetic mutations, but the search for additional variants continues. Many porphyrias remain unexplained. Also, porphyrias show variable genetic penetrance. Additional causative, contributing, and modifier genes are suspected.

To find additional variants, a team of scientists based at Boston Children’s Hospital has been digging into the genome, using a technique called deep sequencing. These scientists have found an additional gene that promotes EPP, highlighting how a complex gene network contributes to disorders of heme metabolism.

Details came to light September 5 in the Proceedings of the National Academy of Sciences, in an article entitled “Mutation in Human CLPX Elevates Levels of δ-Aminolevulinate Synthase and Protoporphyrin IX to Promote Erythropoietic Protoporphyria.” The article describes reports a human familial mutation in a gene called CLPX that contributes to EPP.

Specifically, the Boston Children’s team, which was led by Barry Paw, M.D., Ph.D., of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, performed deep gene sequencing on members of a family from northern France with EPP of a previously unknown genetic signature. Ultimately, Dr. Paw's team discovered a novel mutation in CLPX, which plays a role in mitochondrial protein folding.

“Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX),” wrote the article’s authors. “Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family.”

EPP, the most common kind of porphyria to occur in childhood, causes people's skin to become very sensitive to light. Prolonged exposure to sunshine can cause painful, disfiguring blisters.

“The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT [wild-type] protomers to form an enzyme with reduced activity,” the article’s authors continued. “The presence of low-activity CLPX increases the posttranslational stability of ALAS [δ-aminolevulinate synthase], causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX.”

To produce heme, the body goes through a process called porphyrin synthesis, which mainly occurs in the liver and bone marrow. Any genetic defects that impact this process can interrupt the body's ability to produce heme; the decreased heme production leads to a buildup of protoporphyrin components. In the case of EPP, a type of protoporphyrin called protoporphrin IX accumulates in the red blood cells, plasma, and sometimes the liver.

When protoporphin IX is exposed to light, it produces chemicals that damage surrounding cells. As a result, people with EPP experience swelling, burning, and redness of the skin after exposure to sunlight—even trace amounts of sunlight that pass through window glass.

Some genetic pathways leading to build-up of protoporphyrin IX have already been described, but many cases of EPP remain unexplained. The mutation discovered by Dr. Paw’s team highlights the complex genetic network that underpins heme metabolism. “Loss-of-function mutations,” noted Dr. Paw, “in any number of genes that are part of this network can result in devastating, disfiguring disorders.”

Dr. Paw suggested that identifying the various gene mutations that contribute to porphyria could pave the way for future therapies that could correct the faulty genes responsible for these related disorders.

“Although vampires aren't real, there is a real need for innovative therapies to improve the lives of people with porphyrias,” concluded Dr. Paw.