Letter | Published:

Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice

Nature Genetics volume 39, pages 10251032 (2007) | Download Citation


We undertook a quantitative trait locus (QTL) analysis in mice to identify modifier genes that might influence the severity of human iron disorders. We identified a strong QTL on mouse chromosome 9 that differentially affected macrophage iron burden in C57BL/10J and SWR/J mice. A C57BL/10J missense allele of an evolutionarily conserved gene, Mon1a, cosegregated with the QTL in congenic mouse lines. We present evidence that Mon1a is involved in trafficking of ferroportin, the major mammalian iron exporter, to the surface of iron-recycling macrophages. Differences in amounts of surface ferroportin correlate with differences in cellular iron content. Mon1a is also important for trafficking of cell-surface and secreted molecules unrelated to iron metabolism, suggesting that it has a fundamental role in the mammalian secretory apparatus.

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We thank F. Canonne-Hergaux (INSERM) and D. Haile (University of Texas) for providing antiserum specific to ferroportin, P. Ney for providing Sf-Stk transgenic mouse tissue samples for analysis, A. Donovan for advice on ferroportin analysis and members of the Andrews and Fleming laboratories for discussions. This work was supported by US National Institutes of Health (NIH) R01 grants to N.C.A. and J.K. F.W. was partially supported by funds from a Genome Canada grant obtained by Xenon Pharmaceuticals on which N.C.A. and M.D.F. served as co-investigators. K.A.R. is supported by an NIH training grant.

Author information


  1. Division of Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts, 02115 USA.

    • Fudi Wang
    • , Angel O Custodio
    • , Kristina A Roberts
    •  & Nancy C Andrews
  2. Harvard Medical School, Boston, Massachusetts, 02115 USA.

    • Fudi Wang
    • , Angel O Custodio
    • , Mark D Fleming
    • , Kristina A Roberts
    •  & Nancy C Andrews
  3. Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, 84132 USA.

    • Prasad N Paradkar
    • , Diane McVey Ward
    •  & Jerry Kaplan
  4. Department of Pathology, Children's Hospital Boston, Boston, Massachusetts, 02115 USA.

    • Mark D Fleming
    •  & Dean Campagna
  5. Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, 01655 USA.

    • Victor Boyartchuk
  6. Novartis Institutes for Biomedical Research, Models of Disease Center, Cambridge, Massachusetts, 02139 USA.

    • William F Dietrich


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F.W. developed and analyzed congenic mice, identified candidate genes, characterized Mon1a function and helped write the manuscript. A.O.C. performed the QTL analysis and developed the initial congenic lines. D.M.W., P.P. and J.K. examined the activity of Mon1a in ΔMon1p yeast and in primary macrophages treated with siRNA. P.N.P. carried out biotinylation experiments and ferritin assays. D.C. assisted with fine mapping of DNA samples from congenic mice. M.D.F., K.A.R., V.B. and W.F.D. assisted in the design and interpretation of QTL mapping experiments. N.C.A. guided the overall direction of the studies reported and assisted F.W. in preparing the manuscript.

Competing interests

W.F.D. is now an employee of Novartis. At the time of the collaboration that generated this work, he was a faculty member at Harvard Medical School. F.W. received salary from a Genome Canada grant that passed through Xenon Pharmaceuticals, but Xenon was not involved in this work. No patent application has been filed, though it is possible that the investigators at Children's Hospital and the University of Utah may do so in the future. As the corresponding author, N.C.A. knows of no other real or potential conflicts.

Corresponding author

Correspondence to Nancy C Andrews.

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