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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2001-12-0283. This Article Full Text (PDF) All Versions of this Article: 2001-12-0283v1 100/4/1470    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Magness, S. T Articles by Brenner, D. A Search for Related Content PubMed PubMed Citation Articles by Magness, S. T Articles by Brenner, D. A Social Bookmarking                   What's this? Submitted December 19, 2001 Accepted April 3, 2002 An exon 10 deletion in the mouse ferrochelatase gene has a dominant-negative effect and causes mild protoporphyria Scott T Magness, Nobuyo Maeda, and David A Brenner* Departments of Medicine, Pathology, and Biophysics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA * Corresponding author; email: dab{at}med.unc.edu. Protoporphyria is generally inherited as an autosomal dominant disorder. The enzymatic defect of protoporphyria is a deficiency in ferrochelatase, which chelates iron and protoporphyrin IX to form heme. Patients with protoporphyria have decreased ferrochelatase activities that range from 5%-30% of normal caused by heterogeneous mutations in the ferrochelatase gene. The molecular mechanism by which the ferrochelatase activity is decreased to less than an expected 50% is unresolved. In this study we assessed the effect of a ferrochelatase exon 10-deletion, a common mutation in human protoporphyria, introduced into the mouse by gene targeting. F1 crosses produced (+/+), (+/-), and (-/-) mice at a ratio of 1:2:0; (-/-) embryos were detected at 3.5 days post-coitus (d.p.c), consistent with embryonic lethality for the homozygous mutant genotype. Heterozygotes demonstrated equivalent levels of wild type and mutant ferrochelatase mRNAs, and two immuno-reactive proteins that corresponded to the full-length and an exon 10-deleted ferrochelatase protein. Ferrochelatase activities in the heterozygotes were an average of 37% of normal, and protoporphyrin levels were elevated in erythrocytes and bile. Heterozygous mice exhibited skin photosensitivity but no liver disease. These results lend support for a "dominant-negative" effect of a mutant allele on ferrochelatase activity in patients with protoporphyria. 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