An exon 10 deletion in the mouse ferrochelatase gene has a dominant-negative effect and causes mild protoporphyria - PubMed (original) (raw)
. 2002 Aug 15;100(4):1470-7.
doi: 10.1182/blood-2001-12-0283.
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- PMID: 12149233
- DOI: 10.1182/blood-2001-12-0283
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An exon 10 deletion in the mouse ferrochelatase gene has a dominant-negative effect and causes mild protoporphyria
Scott T Magness et al. Blood. 2002.
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Abstract
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.
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