CoChat
Sign Up
Cited by 1,084Iron Metabolism and DisordersTrace Elements in HealthNeurological diseases and metabolism

Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse

Vulpe, Christopher D., Kuo, Yien-Ming, Murphy, Therese L., Cowley, Lex, Askwith, Candice, Libina, Natasha, Gitschier, Jane, Anderson, Gregory J.·1999·Nature Genetics
DOI 10.1038/5979
Open this paper in CoChat — free account

Abstract

Iron is essential for many cellular functions; consequently, disturbances of iron homeostasis, leading to either iron deficiency or iron overload, can have significant clinical consequences. Despite the clinical prevalence of these disorders, the mechanism by which dietary iron is absorbed into the body is poorly understood. We have identified a key component in intestinal iron transport by study of the sex-linked anaemia (sla) mouse, which has a block in intestinal iron transport. Mice carrying the sla mutation develop moderate to severe microcytic hypochromic anaemia. Although these mice take up iron from the intestinal lumen into mature epithelial cells normally, the subsequent exit of iron into the circulation is diminished. As a result, iron accumulates in enterocytes and is lost during turnover of the intestinal epithelium. Biochemical studies have failed to identify the underlying difference between sla and normal mice, therefore, we used a genetic approach to identify the gene mutant in sla mice. We describe here a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine. We suggest that the hephaestin protein is a multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it is an important link between copper and iron metabolism in mammals.

Integrity signals

Registry

Crossref · 10.1038/5979

Cites

26 of 26 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • After export by FPN1, iron is reoxidized to its ferric form by membrane-anchored hephaestin or by circulating ceruloplasmin.

    “After export by FPN1, iron is reoxidized to its ferric form by membrane-anchored hephaestin or by circulating ceruloplasmin (McKie et al., 2000;Vulpe et al., 1999).”

    From Iron in infection and immunity (2020) · cites this paper as Vulpe et al., 1999

  • The release of iron from enterocytes is controlled by ferroportin followed by extracellular oxidation to ferric iron by hephaestin.

    “This latter step is controlled by the iron exporter, ferroportin (FPN, also called SLC40A1) followed by extracellular oxidation to ferric iron by the copper enzyme hephaestin (HEPH) (Vulpe et al., 1999; Muckenthaler et al., 2017).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Vulpe et al., 1999

  • At the outer cell membrane, iron is oxidized to Fe3+ by ceruloplasmin, hephaestin, and zyklopen.

    “At the outer cell membrane iron is oxidized to its ferric (Fe3+) form by three iron oxidases each displaying distinct expression patterns—ceruloplasmin (CP) (Miller and Cohen, 2001), hephaestin (HEPH) (Vulpe et al., 1999), and zyklopen (HEPHL1) (Chen et al., 2010; Figure 1).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Vulpe et al., 1999

  • Immediately after crossing the basolateral membrane, Fe2+ is oxidized to Fe3+ by hephaestin, a multicopper oxidase co-localized with FPN.

    “Immediately after crossing the basolateral membrane, Fe2+ is oxidized to Fe3+ by hephaestin, a multicopper oxidase co‐localized with FPN. 25 , 26”

    From The battle for iron in enteric infections (2020) · cites this paper as [26]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Vulpe, C. D., Kuo, Y.-M., Murphy, T. L., Cowley, L., Askwith, C., Libina, N., Gitschier, J., & Anderson, G. J.
Affiliations
  • University of California, San Francisco (US)
  • The University of Queensland (AU)
  • University of Utah (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Gitschier, Jane
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
1999-02
Volume
21
Issue
2
Pages
195-199
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/5979
OpenAlex
W2132863560
Cited by
1,084
References
26
Citations by year
2026: 17 · 2025: 13 · 2024: 20 · 2023: 27 · 2022: 26 · 2021: 32 · 2020: 35 · 2019: 30 · 2018: 35 · 2017: 24 · 2016: 25 · 2015: 23 · 2014: 48 · 2013: 40 · 2012: 43
FWCI
33.59
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
hephaestin, intestinal iron transport, microcytic hypochromic anemia, iron homeostasis, copper metabolism, iron overload, iron deficiency, gene identification
MeSH terms
Amino Acid Sequence, Animals, Biological Transport, Ceruloplasmin, Chromosome Mapping, Cloning, Molecular, Humans, Intestinal Mucosa, Iron, Membrane Proteins, Mice, Inbred C57BL, Mice, Mutant Strains, Molecular Sequence Data, Sequence Homology, Amino Acid, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review