Poblete-Gutiérrez P1, Wiederholt T1, Martinez-Mir A2, Merk HF3, Connor JM4, Christiano AM5, Frank J6
1Department of Dermatology and Allergology and Porphyria Center and Interdisciplinary Center for Clinical Research, University Clinic of the RWTH Aachen, Aachen, Germany, 2Department of Dermatology, Columbia University, New York, USA, 3Department of Dermatology and Allergology, University Clinic of the RWTH Aachen, 4Duncan Guthrie Institute of Medical Genetics, Glasgow, UK, 5Departments of Dermatology and Genetics and Development, Columbia University, New York, USA, 6Department of Dermatology and Allergology and Porphyria Center, University Clinic of the RWTH Aachen, Aachen, Germany
The porphyrias are disorders arising from predominantly inherited catalytic deficiencies of one of the eight enzymes along the heme biosynthetic pathway. All genes encoding these enzymes have been cloned and several mutations underlying the different types of porphyrias have been reported. The diagnosis of porphyria is traditionally made on the basis of clinical symptoms, characteristic biochemical findings, and specific enzyme essays. In some cases however, these diagnostic tools reveal overlapping data, indicating the existence of dual porphyrias with two enzymes of heme biosynthesis being deficient simultaneously. Recently, it was reported that the so called Chester porphyria shows attributes of both variegate porphyria and acute intermittent porphyria. Linkage analysis revealed a novel chromosomal locus on chromosome 11 for the underlying genetic defect in this disease. For the first time, these data suggested that a gene, which does not encode one of the enzymes of heme biosynthesis might be involved in the pathogenesis of the porphyrias. After excluding several candidate genes within the originally published new linkage interval, we identified a nonsense mutation in the porphobilinogen deaminase gene, which harbors the mutations causing acute intermittent porphyria, as the underlying genetic defect in Chester porphyria. However, we could not detect a mutation in the coding or the promotor region of the protoporphyrinogen oxidase gene that is mutated in variegate porphyria. Our results indicate that Chester porphyria is neither a dual porphyria, nor a separate type of porphyria, and also exclude the possibility that a hitherto unknown gene is involved in the pathogenesis of this disorders. We suggest that all so-called dual porphyrias should be studied on the molecular genetic level before claiming their existence.