Erythropoietic protoporphyria (EPP) with mild or no liver disease can be caused by two co-occurring mutations in the FECH gene, researchers report. One of the two mutations has not previously been described.
Their study, “Characterization of a novel pathogenic variant in the FECH gene associated with erythropoietic protoporphyria” was published in the journal Molecular Genetics and Metabolism Reports.
Erythropoietic protoporphyria (EPP) is a type of porphyria caused by mutation in the FECH gene. The gene is located on chromosome 18 (a non-sex chromosome) and carries the instructions to make the enzyme ferrochelatase.
This enzyme is involved in the production of heme, a molecule of extreme importance for organ health. Heme is an essential part of various proteins including hemoglobin, responsible for carrying oxygen in the blood.
Lack of this enzyme leads to the toxic accumulation of protoporphyrin in the body. This leads to liver damage and extreme sensitivity to sunlight, the characteristic symptoms of people with EPP.
More than 90% of EPP patients have the same mutation (c.315-48T>C) in the FECH gene.
In this study, the researchers tested a family of Northern European ancestry in which three family members exhibited extreme painful sensitivity to sunlight and were diagnosed with EPP. They had little to no liver involvement. Genetic testing was performed on seven members of the family to understand the inheritance and genetic basis of their disease.
Researchers identified a new mutation (c.904_912+1del) in the three siblings (59–66 years old) who also carried the common c.315-48T>C mutation. The two variations were found in trans, i.e., they were on different copies of the FECH gene. Of note, people inherit two copies of each autosomal (located in a non-sex chromosome) gene, one from each parent.
The new mutation resulted in the deletion of a portion of the FECH gene between locations 904 to 912 on the coding sequence of the gene.
In the three patients, the protoporphyrin levels were also extremely high (>2000 μg/dl); in the family members not affected by the disease, the levels ranged from 90–100 μg/dl.
Researchers assessed the impact of the new mutation on protein synthesized from this mutated gene and found that this deletion resulted in the formation of a truncated (shortened) FECH protein.
“Genetic, biochemical, and functional assay results obtained for this family suggest that the unique variant c.904_912+1del is likely [disease causing] and thus causative of EPP,” the researchers concluded.