Molecular studies of liver disease in erythropoietic protoporphyria.
OBJECTIVE
The goal of this study was to define molecular determinants of liver disease in erythropoietic protoporphyria (EPP).


BACKGROUND
EPP is a genetic disorder in which deficient ferrochelatase activity causes excessive production of protoporphyrin, which is excreted in bile. Some patients develop liver disease that necessitates transplantation.


METHODS
Ferrochelatase gene analysis was done in 25 families with EPP to identify mutations and a polymorphism (IVS3-48c) that causes low gene expression. Expression of multiple hepatic genes was also examined by DNA microarray analysis in patients who had liver transplantation to identify genes with altered regulation.


RESULTS
Heterozygous ferrochelatase mutations were found in 43 individuals. In 94% of 31 symptomatic patients, 15 of whom had liver disease, the polymorphism was also present in the nonmutant allele. Explanted liver of patients who had transplantation showed significant change in expression of several genes involved in wound healing, organic anion transport, and oxidative stress.


CONCLUSIONS
Patients with EPP who develop liver disease usually have a mutation in one ferrochelatase allele that alters enzyme function, together with a polymorphism in the nonmutant allele that causes low gene expression. This results in significant increase in the hepatobiliary excretion of protoporphyrin, which can damage the liver through both cholestatic injury and oxidative stress.
Bloomer
Joseph
J
Liver Center, Departments of Medicine and Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA. jbloomer@uabmc.edu
Wang
Yongming
Y
Singhal
Anuj
A
Risheg
Hiba
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005260:Female; D005294:Ferrochelatase / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008107:Liver Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D046351:Protoporphyria, Erythropoietic / Q000235:genetics*; D011524:Protoporphyrins / Q000378:metabolism
D011524:Protoporphyrins; D005294:Ferrochelatase