Barman-Aksözen J C Wiek P Bansode VB Koentgen F Trüb J Pelczar P Cinelli P Schneider-Yin X Schümperli D Minder EI 2017 Erythropoietic protoporphyria (EPP) is caused by deficiency of ferrochelatase (FECH), which incorporates iron into protoporphyrin IX (PPIX) to form heme. Excitation of accumulated PPIX by light generates oxygen radicals that evoke excessive pain and, after longer light exposure, cause ulcerations in exposed skin areas of individuals with EPP. Moreover, ∼5% of the patients develop a liver dysfunction as a result of PPIX accumulation. Most patients (∼97%) have a severe FECH mutation (Mut) in trans to an intronic polymorphism (c.315-48C), which reduces ferrochelatase synthesis by stimulating the use of an aberrant 3' splice site 63 nt upstream of the normal site for exon 4. In contrast, with the predominant c.315-48T allele, the correct splice site is mostly used, and individuals with a T/Mut genotype do not develop EPP symptoms. Thus, the C allele is a potential target for therapeutic approaches that modify this splicing decision. To provide a model for pre-clinical studies of such approaches, we engineered a mouse containing a partly humanized Fech gene with the c.315-48C polymorphism. F1 hybrids obtained by crossing these mice with another inbred line carrying a severe Fech mutation (named m1Pas) show a very strong EPP phenotype that includes elevated PPIX in the blood, enlargement of liver and spleen, anemia, as well as strong pain reactions and skin lesions after a short period of light exposure. In addition to the expected use of the aberrant splice site, the mice also show a strong skipping of the partly humanized exon 3. This will limit the use of this model for certain applications and illustrates that engineering of a hybrid gene may have unforeseeable consequences on its splicing. application/pdf https://sonar.ch/global/documents/173601 eng info:eu-repo/semantics/altIdentifier/doi/10.1242/dmm.027755 info:eu-repo/semantics/altIdentifier/pmid/28093505 info:eu-repo/semantics/openAccess Disease models & mechanisms. - 2017 Liver dysfunction Mouse model Photosensitivity Protoporphyrin IX (PPIX) Rare disease Splicing defect Alleles Alternative Splicing Animals Base Sequence Blood Cells Breeding Disease Models, Animal Exons Ferrochelatase Genotype Homologous Recombination Humans Light Liver Mice, Inbred C57BL Mice, Transgenic Mutation Organ Size Protoporphyria, Erythropoietic RNA, Messenger Skin Modeling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice. http://purl.org/coar/resource_type/c_6501