Photosensitive blood disorders: New genetic mutation may be the cause

Medical Genetics

A new study published in Proceedings of the National Academy of Science exposed a new gene responsible for erythropoietic protoporphyria (EPP).

Erythropoietic protoporphyria is a photosensitive blood disorder. Previously, the disorder was believed to be caused by two specific genes, but using an extended pedigree from France, researchers found that changes in another gene are responsible for the EPP.

The research team led by BWH chief investigator Barry Paw, of the Division of Newborn Medicine and Hematology, explained a mechanism, which contributes EPP by producing a high level of porphyrin. The excessive porphyrin (a protein in RBC) was found to be due to the functional defects caused by the mutation of gene CLPX.

The researchers recognized a proband — a person serving as the starting point for the genetic study — of the family from Northern France, with EPP of unknown genetic signature and analyzed the data collected from the proband. The study found that proband had an unusual form of EPP. Even proband's father and uncle found with indicators linked with mild photosensitivity, but there were no clinical symptoms of EPP observed.

CLPX gene plays a vital role in mitochondrial protein folding, as it controls the mitochondrial unfoldase, an enzyme that accounts for the unfolding of selected proteins for protein quality control. It commences the heme biosynthesis by catalytically activating an essential enzyme called δ-aminolevulinate synthase (ALAS) or degrading ALAS protein.

The researchers found a reduced degradation of ALAS protein since the dominant mutation occurred in CLPX inherited by members of that family. The reduced degradation led to the buildup of protoporphyrin IX (PPIX), which is known to result in EPP.

A previous study led by the team revealed that mitochondrial AAA+ unfoldase and ClpX were the two specific genes that promoting PPIX overproduction and EPP. But, the current research finds another gene supporting EPP and continues to expand the complex gene network that relates to heme metabolism disorders.

The researchers conclude, “We hope that further understanding of the complex network of enzyme and cofactor interactions controlling heme synthesis will continue to contribute ideas for therapeutic strategies to treat diseases caused by aberrant regulation of heme metabolism.”