Inheritance in Erythropoietic Protoporphyria: A Common Wild-Type Ferrochelatase Allelic Variant With Low Expression Accounts for Clinical Manifestation

摘要: Erythropoietic protoporphyria (EPP) is a rare autosomal dominant disorder of heme biosynthesis characterized by partial decrease in ferrochelatase (FECH; EC [4.99.1.1][1]) activity with protoporphyrin overproduction and consequent painful skin photosensitivity rarely liver disease. EPP normally inherited an pattern low clinical penetrance; the many different mutations that have been identified are restricted to one FECH allele, other being free any mutations. However, manifestations cannot be simply matter haploinsufficiency, because patients enzyme levels lower than expected 50%. From RNA analysis family EPP, we recently suggested expression required coinheritance normal allele mutant allele. We now show (1) gene defect wild-type low-expressed generally involved EPP; (2) allelic variant was strongly associated 5′ haplotype [ −251G IVS1−23T IVS2μsatA9 ] may ancestral present estimated 10% control group Caucasian origin; (3) haplotyping allows absolute risk developing disease predicted for those inheriting thus considered as does not strictly follow recessive or rules. It represent model phenotype modulation mild variation diseases. [1]: pending:yes