Molecular characterization of erythropoietic protoporphyria in South Africa

Summary Background Erythropoietic protoporphyria (EPP) results from a partial deficiency of ferrochelatase (FECH). Clinical expression normally requires coinheritance of a common hypomorphic FECH allele (IVS3‐48C) in trans to a deleterious (primary) FECH mutation. Objectives To characterize South African subjects with EPP, by identification and assessment of FECH sequence variations, including the IVS3‐48C polymorphism. Methods Polymerase chain reaction amplification, single‐strand conformational polymorphism analysis and restriction endonuclease analysis were employed to identify and determine the frequencies of FECH sequence variations, including the IVS3‐48C polymorphism, in a study cohort of symptomatic and asymptomatic South African EPP family members, and a matched control cohort. Results We identified 29 patients from 18 families. With the exception of one family, who may represent a phenocopy of EPP, the presentation of EPP was typical. All were of European immigrant stock, and we have not identified EPP in other ethnic groups. Ten sequence variations were identified, including four apparent disease‐causing mutations, the IVS3‐48T/C polymorphism and five further polymorphisms. The molecular basis of EPP was established for 15 of the 17 families. A 5‐bp deletion in exon 7 (757_761delAGAAG) was present in 12 of these families and haplotype studies in these families suggested a single mutational event and thus a local founder effect for this deletion. The other mutations were family specific and included two previously described splice‐site mutations (IVS3+2T>G and IVS7+1G>A) and a novel 7‐bp deletion in exon 4 (356_362delTTCAAGA). Conclusions The IVS3‐48C allele appears to modulate the phenotypic expression of EPP in the South African EPP cohort as observed in other populations.