Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease

Abstract

To study the mutations in the ferrochelatase gene (FECH) and the phenotypic expression of erythropoietic protoporphyria (EPP) in a group of Spanish patients. Design: Case series. Setting: University-based hospital. Patients: Eleven unrelated patients with EPP and 19 asymptomatic relatives from 10 families. Main Outcomes Measures: Measurement of protoporphyrin concentration in red blood cells and feces by fluorometry and chromatography. Analysis of the mutations of the FECH gene by single-strand conformation analysis. Expression of mutations in Escherichia coli.Results: FECH gene mutations were found in all 11 patients. Ten were heterozygous and carried the IVS3-48C low-expression allele. Three novel mutations were found: IVS4ϩ 1delG, 347-351delC, and 130_147dupl 18. One

Novel Null-Allele Mutations and Genotype-Phenotype Correlation in Argentinean Patients with Erythropoietic Protoporphyria

“…These findings are in agreement with the conclusion that the inheritance of a lowexpressed allele together with the mutation in the FECH gene are necessary for the clinical expression of this porphyria (4,13,14,16,(25)(26)(27).…”

“…Although the inheritance of an IVS3-48C allele trans to the mutation explained the phenotypic expression in most families (4,(12)(13)(14), autosomal recessive inheritance can cause overt EPP in patients who do not have the low- expression allele. A small number of cases of recessive inheritance have been reported (15,16). To date, EPP has been diagnosed in 41 individuals from 35 families in our Research Centre on Porphyrins and Porphyrias in Argentina.…”

Iron –sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery

“…The most severe clinical feature is hepatobiliary disease due to protoporphyrin- induced damage to liver cells [298]. Deficiency of the Fe-S enzyme ferrochelatase (FECH), which catalyzes the insertion of ferrous iron into protoporphyrin to form heme, is the most common cause of EPP [299–301]. A variant form of EPP has been linked to aberrant splicing of MFRN1 mRNA, which encodes the erythroblastic specific solute carrier mitoferrin 1 (MFRN1, SLC25A37), the major importer of iron into mitochondria in erythroblastic cells [302].…”

Eryhtropoietic Protoporphyria

“…15 In Spain, Herrero reported that three novel mutations (IVS4+1delG, 347-351delC, and 130_147dupl 18) and IVS3-48C low-expression allele in ten of 11 EPP patients. 26 They also estimated the frequency of the IVS3-48C allele among 180 nonporphyric Spanish individuals as 5.2%. 26 In South Africa, Parker identified ten sequence variations; IVS3-48T ⁄ C polymorphism, five further polymorphisms, a 5-bp deletion in exon 7 (757_761delAGAAG), two previously described splice-site mutations (IVS3+2T>G and IVS7+1G>A), and a novel 7-bp deletion in exon 4 (356_362delTTCAAGA).…”

“…26 They also estimated the frequency of the IVS3-48C allele among 180 nonporphyric Spanish individuals as 5.2%. 26 In South Africa, Parker identified ten sequence variations; IVS3-48T ⁄ C polymorphism, five further polymorphisms, a 5-bp deletion in exon 7 (757_761delAGAAG), two previously described splice-site mutations (IVS3+2T>G and IVS7+1G>A), and a novel 7-bp deletion in exon 4 (356_362delTTCAAGA). 27 In Portugal, Morais identified heterozygosity for a novel mutation (c.1052delA) in FECH gene of two children, and heterozygosity for the hypomorphic allele IVS3-48T>C in two children and asymptomatic mother.…”