title: A 10376 bp deletion of FECH gene responsible for erythropoietic protoporphyria.
abstract: Erythropoietic protoporphyria (EPP, MIM 177000) is an autosomal dominant disease with incomplete penetrance since the phenotypic expression requires coinheritance of a null allele and a wild-type low expressed allele of Ferrochelatase gene (FECH). In this study, we identify a peculiar mutation in a young Canadian patient of Italian origin. The patient had clinical and biochemical symptoms of EPP, the wild-type low expressed allele but at preliminary analysis no mutation in the promoter, in the entire coding region and in the splice junctions of the gene. Family studies of seven most common polymorphisms along the gene established absence of Mendelian segregation for the promoter polymorphism only. The intron 1 polymorphism appeared in heterozygosis suggesting an hypothetical deletion in the first region of the gene. In order to identify the size of this deletion, single nucleotide polymorphisms (SNPs) analysis was extended to the upstream N-asparaginyl-tRNA synthetase gene (NARS). We analyzed two polymorphisms in the last exon of this gene and a dizigous region was found in the patient. A Long-PCR with primers located in previously fixed heterozygous regions showed a 10,376 bp deletion (c.1-7887_67+2422del) that included a portion of the upstream intergenic region, the promoter, the exon 1 and a portion of intron 1. RNA analysis demonstrated that the lack of the entire promoter prevents the expression of the mutated allele, in fact the expression of the Ferrochelatase gene was decreased by half in the subjects carrying only the mutation compared to control.
authors: Department of Internal Medicine, University of Milan-Maggiore Policlinico, Mangiagalli and Regina Elena Hospital, Foundation IRCCS, Italy.
authors: Elena
authors: E
authors: Di Pierro
authors: Valentina
authors: V
authors: Brancaleoni
authors: Valeria
authors: V
authors: Besana
authors: Sabrina
authors: S
authors: Ausenda
authors: Stella
authors: S
authors: Drury
authors: Maria Domenica
authors: MD
authors: Cappellini
mesh_terms: D000483:Alleles; D002648:Child; D005294:Ferrochelatase / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D046351:Protoporphyria, Erythropoietic / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D005294:Ferrochelatase