Linking hypoxia and iron homeostasis: a ‘plate’ full of factors

Subramaniam, V. Nathan; Wallace, Daniel F.

doi:10.1136/gutjnl-2014-306970

Cited by 1 publication

(1 citation statement)

References 13 publications

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“…HAMP mRNA expression was significantly lower in GNPAT ‐silenced cells treated with BMP6, suggesting that GNPAT‐mediated effects on HAMP may be independent of the BMP‐SMAD pathway. HAMP is regulated by many factors, such as hypoxia, erythroid factors, and inflammation, that act through signaling pathways independent of BMP‐SMAD . It is possible that GNPAT knockdown modifies components of any, or a combination of, these pathways, with consequent downstream effects on hepcidin and, ultimately, iron homeostasis, such as regulation of intestinal iron absorption.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload

McLaren¹,

Emond²,

Subramaniam

et al. 2015

Hepatology

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To identify polymorphisms associated with variability of iron overload severity in HFE-associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n=22; cases) or with normal or mildly increased iron stores (n=13; controls). The 35 participants, residents of the U.S., Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (p = 3×10−6, p=0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of 22 participants with severe iron overload had GNPAT polymorphism p.D519G (rs11558492) (15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed siRNA-based knockdown of GNPAT in the human liver-derived cell line HepG2/C3A. This knockdown resulted in a >17-fold decrease in expression of the mRNA encoding the iron regulatory hormone hepcidin. Conclusion: GNPAT p.D519G is associated with a high-iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation.

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Section: Discussionmentioning

confidence: 99%