Protoporphyria (EPP) is a genetic disorder in which deficient activity of the mitochondrial enzyme ferrochelatase (FECH) causes excessive accumulation of protoporphyrin. As a consequence patients have photosensitivity which is variable in degree, and some develop liver disease. Molecular studies from this and other laboratories have shown that most patients are heterozygous for FECH gene mutations which do not explain the phenotypic variation. The major objective of this proposal is to examine the hypothesis that the level of expression of the FECH allele which encodes normal protein (nonmutant allele), is also a critical factor. In the first specific aim families in which members have different phenotypic expression of EPP will be studied to determine whether inheritance of a low-expressing nonmutant FECH """"""""allele, together with the mutant FECH allele, has occurred in those with symptomatic EPP. Haplotype analysis will distinguish mutant from nonmutant alleles, and the level of normal FECH mRNA will be specifically assessed in cultured lymphoblasts. The presence of an intron polymorphism associated with aberrantly spliced FECH mRNA that is rapidly degraded will be examined for in the nonmutant allele. The promoter region and more extended 5'- untranslated region of the nonmutant FECH allele will also be sequenced and expressed in an in vitro system. In the second specific aim, a mouse model of EPP in which there is a heterozygous deletion of exon 10 will be backcrossed with inbred strains of mice which are selected for different levels of FECH gene expression on the basis of FECH activity and FECH mRNA levels in liver and bone marrow. It is anticipated that the level of FECH activity, and hence degree of protoporphyrin accumulation, will vary in heterozygous offspring according to the level of FECH gene expression in the wild-type parent. Liver and bone marrow will be assessed for FECH activity, FECH mRNA, and levels of normal and mutant FECH proteins. Liver mitochondria will be examined for the presence of heterodimers consisting of the normal and mutant FECH proteins. Phenotype will be assessed by the protoporphyrin levels, and degree of photosensitivity and liver damage. The proposal thus is designed to define a critical relationship between FECH gene expression and phenotype in EPP which will lead to better genetic counseling and therapy.
| Wang, Yongming; Langer, Nathaniel B; Shaw, George C et al. (2011) Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria. Exp Hematol 39:784-94 |
| Bloomer, Joseph R; Wang, Yongming; Singhal, Anuj et al. (2006) Biochemical abnormality in erythropoietic protoporphyria: cause and consequences. J Pediatr Gastroenterol Nutr 43 Suppl 1:S36-40 |
| Rand, Elizabeth B; Bunin, Nancy; Cochran, William et al. (2006) Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics 118:e1896-9 |
| McGuire, Brendan M; Bonkovsky, Herbert L; Carithers Jr, Robert L et al. (2005) Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl 11:1590-6 |
| Bloomer, Joseph; Wang, Yongming; Singhal, Anuj et al. (2005) Molecular studies of liver disease in erythropoietic protoporphyria. J Clin Gastroenterol 39:S167-75 |
| Liu, Yunying L; Ang, Sonny O; Weigent, Douglas A et al. (2004) Regulation of ferrochelatase gene expression by hypoxia. Life Sci 75:2035-43 |
| Risheg, Hiba; Chen, Fu-Ping; Bloomer, Joseph R (2003) Genotypic determinants of phenotype in North American patients with erythropoietic protoporphyria. Mol Genet Metab 80:196-206 |
| Chen, Fu-Ping; Risheg, Hiba; Liu, Yunying et al. (2002) Ferrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease. Cell Mol Biol (Noisy-le-grand) 48:83-9 |
| Bloomer, J R; Poh-Fitzpatrick, M B (2000) Theodore Woodward Award. Pathogenesis of biochemical abnormalities in protoporphyria. Trans Am Clin Climatol Assoc 111:245-56; discussion 256-7 |
| Wang, X; Yang, L; Kurtz, L et al. (1999) Haplotype analysis of families with erythropoietic protoporphyria and novel mutations of the ferrochelatase gene. J Invest Dermatol 113:87-92 |
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