Skinbase

Ferrochelatase Deficiency (Fech), Chr. 18, 39.0 cM, Genome Coordinates: 6498828-65009641

The first allele for ferrochelatase deficiency was found in a mutagenesis experiment using ethylnitrosourea at the Institut Pasteur in 1998. A targeted mutation was subsequently created. Studies with the first allele revealed marked variability in the phenotype based on the genetic background. The mutated gene was mapped to Chromosome 18. On the BALB/cByJ background, jaundice can be seen as early as 2 weeks of age by the color of the serum and the yellow color of the unhaired and unpigmented ears. Photosensitivity may be a problem, particularly affecting the ears, under normal husbandry conditions, especially in cages close to the light source. Results vary based on the wavelength of the lamps used. In such cases ears become red and swollen. Tips of the pinna may undergo necrosis, ulceration, and autoamputation. Hepatomegaly and splenomegaly are progressive.

Livers accumulate proporphyrin IX as a brown crystalin material within canaliculi, interlobular biliary ducts, Kupffer cells, and the gall bladder. There is progressive portal and periportal fibrosis associated with increased pigment. Erythroid hyperplasia is a prominent feature in the spleen and bone marrow. Mice develop a normocytic anemia. Polychromasia, anisocytosis, target cells, and leptocytes can be found in blood smears.

This is a mouse model for human erythropoeitic protoporphyria (EPP) which is also associated with reduced activity of ferrochelatase.

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Taketani S; Fujita H, The ferrochelatase gene structure and molecular defects associated with erythropoietic protoporphyria., J Bioenerg Biomembr 1995 Apr;27(2):231-8

Shivdasani RA; Orkin SH, Erythropoiesis and globin gene expression in mice lacking the transcription factor NF-E2., Proc Natl Acad Sci U S A 1995 Sep 12;92(19):8690-4

Ferreira GC, Ferrochelatase binds the iron-responsive element present in the erythroid 5-aminolevulinate synthase mRNA., Biochem Biophys Res Commun 1995 Sep 25;214(3):875-8

Sellers VM; Johnson MK; Dailey HA, Function of the [2FE-2S] cluster in mammalian ferrochelatase: a possible role as a nitric oxide sensor., Biochemistry 1996 Feb 27;35(8):2699-704

Crouse BR; Sellers VM; Finnegan MG; Dailey HA; Johnson MK, Site-directed mutagenesis and spectroscopic characterization of human ferrochelatase: identification of residues coordinating the [2Fe-2S] cluster., Biochemistry 1996 Dec 17;35(50):16222-9

Magness ST; Brenner DA, Targeted disruption of the mouse ferrochelatase gene producing an exon 10 deletion., Biochim Biophys Acta 1999 Jan 6;1453(1):161-74

Taketani S; Mohri T; Hioki K; Tokunaga R; Kohno H, Structure and transcriptional regulation of the mouse ferrochelatase gene., Gene 1999 Feb 18;227(2):117-24

Bloks V; Plosch T; van Goor H; Roelofsen H; Baller J; Havinga R; Verkade H; van Tol A; Jansen P; Kuipers F, Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice., J Lipid Res 2001 Jan;42(1):41-50

Magness ST; Maeda N; Brenner DA, An exon 10 deletion in the mouse ferrochelatase gene has a dominant-negative effect and causes mild protoporphyria., Blood 2002 Aug 15;100(4):1470-7

Libbrecht L; Meerman L; Kuipers F; Roskams T; Desmet V; Jansen P, Liver pathology and hepatocarcinogenesis in a long-term mouse model of erythropoietic protoporphyria., J Pathol 2003 Feb;199(2):191-200

Shi Z; Ferreira GC, Probing the active site loop motif of murine ferrochelatase by random mutagenesis., J Biol Chem 2004 May 7;279(19):19977-86