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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 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 Citation Map 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. Related Collections Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2002, Vol. 100, No. 4, pp. 1470-1477 RED CELLS 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 From the Departments of Medicine, Pathology, and Biochemistry and Biophysics, University of North Carolina at Chapel Hill. 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% to 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 postcoitus, consistent with embryonic lethality for the homozygous mutant genotype. Heterozygotes demonstrated equivalent levels of wild-type and mutant ferrochelatase messenger RNAs and 2 immunoreactive 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. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Lynch, Y. Fukuda, P. Krishnamurthy, G. Du, and J. D. Schuetz Cell Survival under Stress Is Enhanced by a Mitochondrial ATP-Binding Cassette Transporter That Regulates Hemoproteins Cancer Res., July 1, 2009; 69(13): 5560 - 5567. [Abstract] [Full Text] [PDF] A V Anstey and R J Hift Liver disease in erythropoietic protoporphyria: insights and implications for management Postgrad. Med. J., December 1, 2007; 83(986): 739 - 748. [Full Text] [PDF] K. E. R. Gooijert, R. Havinga, A. R. Oosterloo-Duinkerken, E. E. A. Venekamp-Hoolsema, F. Kuipers, and H. J. 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	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020