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Dis Model Mech. 2017 Mar 1;10(3):225-233. doi: 10.1242/dmm.027755. Epub 2017 Jan 12.

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

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Institute of Laboratory Medicine, Municipal Hospital Triemli, Zürich 8063, Switzerland.
Institute of Cell Biology, University of Bern, Bern 3012, Switzerland.
Ozgene Pty Ltd, Bentley DC, WA 6983, Australia.
Center for Transgenic Models, University of Basel, Basel 4002, Switzerland.
Division of Trauma Surgery, University Hospital Zürich, Zürich 8091, Switzerland.
Institute of Cell Biology, University of Bern, Bern 3012, Switzerland
Institute of Laboratory Medicine, Municipal Hospital Triemli, Zürich 8063, Switzerland
Porphyria Outpatient Clinics, Municipal Hospital Triemli, Zürich 8063, Switzerland.


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.


Liver dysfunction; Mouse model; Photosensitivity; Protoporphyrin IX (PPIX); Rare disease; Splicing defect

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