Homozygosity for the HFE C282Y mutation accounts for approximately 90 percent of HFE-associated (type 1) hereditary hemochromatosis. The clinical phenotype in C282Y homozygotes, however, ranges from simply an elevated percent saturation of transferrin to organ damage due to iron overload. Modifier genes have been proposed to explain this phenotypic variability. Hepatic siderosis is a nearly constant finding in patients with PCT. Approximately 20 percent of patients with PCT are homozygotes for the C282Y HFE mutation but the cause of hepatic iron loading in the remaining 80 percent is not known. Approximately one-third of patients with PCT are heterozygotes for mutations of the uroporphyrinogen decarboxylase (URO-D) gene (familial PCT) but pedigree studies indicate that clinical expression occurs only in those URO-D heterozygotes who develop hepatic siderosis. Most patients with PCT have no URO-D mutations (sporadic PCT) but virtually all sporadic cases have hepatic iron overload. Two genes known to affect iron homeostasis are hepcidin (HAMP) and hemojuvelin (HJV). Heterozygosity for HAMP and HJV mutations have been associated with marked iron overload in a small number of patients with type 1 hemochromatosis (
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 C282Y homozygotes and in PCT patients with or without HFE mutations. We sequenced the HAMP and HJV genes in 96 hemochromatosis patients with grade 3–4 (scale 0–4) hepatic parenchymal cell stainable iron (HPCSI) and 96 PCT patients with variable degrees of hepatic siderosis. Ninety-four percent (90) of the hemochromatosis patients were C282Y homozygotes, 4.2 percent (4) were C282Y heterozygotes and 2.1 percent (2) were wild type 282 homozygotes. 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 at the HFE locus. Twenty-five percent (21) were C282Y homozygotes, 23 percent (19) were C282Y heterozygotes and 52 percent (43) were wild type 282 homozygotes. 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 282 wild type homozygotes 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 hemochromatosis or PCT. Other modifier loci must exist.
Disclosure: No relevant conflicts of interest to declare.
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