Modelling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice.

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Dis Model Mech. 2017 Jan 12. pii: dmm.027755. doi: 10.1242/dmm.027755. [Epub ahead of print]

Modelling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP) in mice.

J Barman-Aksözen;P Ćwiek;VB Bansode;F Koentgen;J Trüb;P Pelczar;P Cinelli;X Schneider-Yin;D Schümperli;EI Minder

Municipal Hospital Triemli, 8063 Zurich, Switzerland. University of Bern, 3012 Bern, Switzerland. Ozgene Pty Ltd, Bentley, Perth, Western Australia, Australia. University of Basel, 4002 Basel, Switzerland. University Hospital Zurich, 8091 Zurich, Switzerland. Municipal Hospital Triemli, 8063 Zurich, Switzerland

Service type: Humanized mice


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 which evoke excessive pain and, after longer light exposure, ulcerations in exposed skin areas of EPP patients. Moreover, ∼5% of the patients develop a liver dysfunction due to 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 which includes elevated PPIX in the blood, enlargement of liver and spleen, anemia, as well as strong pain reactions and skin lesions after short 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.

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