Publication Date:
2014-12-06
Description:
Variability in the severity of iron overload among homozygotes for the HFE C282Y polymorphism is one of the major unsolved problems in our understanding of hereditary hemochromatosis (HH). We previously conducted exome sequencing of DNA from 35 HFE C282Y male homozygotes with either markedly increased iron stores (n=22; cases) or normal to mildly increased iron stores (n=13; controls) to identify rare and common causal variants associated with variability of disease expression in HH. The 35 participants, residents of the U.S., Canada, and Australia, reported little or no alcohol consumption. Criteria for HFE C282Y homozygotes with increased iron stores included serum ferritin 〉1000 µg/L at diagnosis and either (a) hepatic iron concentration 〉236 µmol/g dry weight (reference range 0-36 µmol/g) or (b) mobilized body iron 〉10 g by quantitative phlebotomy. Criteria for HFE C282Y homozygotes with normal or mildly elevated iron stores included (a) serum ferritin 17-fold decrease in HAMP mRNA expression. mRNA expression of two genes coordinately regulated with HAMP, ID1 (inhibitor of DNA binding protein 1) and SMAD7 (SMAD family member 7), was similarly decreased, as was expression of phospho-SMAD 1/5/8, suggesting that GNPAT knockdown affects the baseline activity of the bone morphogenetic protein 6 (BMP6)-SMAD pathway. Our data indicate that GNPAT p.D519G is associated with a high-iron phenotype in male HFE C282Y homozygotes and may participate in hepcidin regulation, thereby modifying severity of iron overload. The results identify GNPAT as a candidate gene for expanded studies to examine its function in regulating iron absorption and metabolism and to identify newly-diagnosed C282Y homozygotes whose risk for development of severe iron overload is great. Disclosures No relevant conflicts of interest to declare.
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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