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  1. R. S. Ajioka1,
  2. J. D. Phillips1,
  3. J. P. Kushner1
  1. 1Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT.


Homozygosity for the HFE C282Y (HFE Y/Y) mutation accounts for approximately 90% of HFE-associated (type 1) hereditary hemochromatosis (hh), but the clinical phenotype ranges from simply an elevated transferrin (Tf) saturation to organ damage due to iron overload. Modifier genes have been proposed to explain this phenotypic variability. A second disease associated with hepatic iron overload is porphyria cutanea tarda (PCT). Approximately 20% of patients with PCT are HFE Y/Y, but the cause of hepatic iron loading in the remaining 80% is not known. Two genes known to affect iron homeostasis are hepcidin (HAMP) and hemojuvelin (HJV). Heterozygosity for HAMP and HJV mutations has been associated with iron overload in a small number of type 1 hh patients (Blood. 2004;103:2835-40; Blood Cells Mol Dis 2004;33:338-43). We asked if mutations of HAMP or HJV could account for hepatic iron overload in highly penetrant hh patients and in PCT patients with or without HFE mutations. Serum iron values did not differ between hh and PCT patients, but Tf saturation and serum ferritin values were higher in hh patients compared with PCT patients with hh. This may reflect the fact that PCT patients develop skin lesions leading to diagnosis at a younger age than organ damage occurs in patients with hh but without PCT. We sequenced the HAMP and HJV genes in 96 hh patients with grade 3 to 4 (scale 0-4) hepatic parenchymal cell stainable iron and 96 PCT patients with variable degrees of hepatic siderosis. Ninety-four percent (90) of the hh patients were HFE Y/Y, 4.2% (4) were HFE C/Y, and 2.1% (2) were wild-type HFE C/C. No exonic changes or splice site mutations were detected in either the HAMP or HJV genes. Eighty-three of the 96 PCT patients were genotyped. Twenty-five percent (21) were HFE Y/Y, 23% (19) were HFE C/Y, and 52% (43) were HFE C/C. No exonic changes or splice site mutations were detected in the HJV gene of patients with PCT, but two PCT patients were found to be heterozygotes for HAMP mutations. The first had the previously identified 212G→A transition leading to a G71D substitution. The second had a 248A→C transversion corresponding to K83R in the peptide. Both of these PCT patients were HFE C/C, but both had grade 4 HPCSI. These data indicate that heterozygosity for mutations of HAMP or HJV rarely modifies the iron loading phenotype in either type 1 hh or PCT. Other modifier loci must exist.

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