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


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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Figure 1: Quantitative measurements of spleen, liver and serum iron concentrations in inbred mouse strains.
Figure 2: Haplotypes and quantitative tissue iron measurements of chromosome 9 congenic strains.
Figure 3: Haplotype panels and candidate genes identified through a backcross of line 5 with SWR/J.
Figure 4: Expression of Mon1a and ferroportin proteins in primary bone marrow–derived macrophages.
Figure 5: Inactivation of Mon1a in macrophages isolated from C57BL/6J mice.
Figure 6: Inactivation of Mon1a prevents secretion of macrophage inhibitory factor.


  1. Andrews, N.C. & Schmidt, P.J. Iron homeostasis. Annu. Rev. Physiol. 69, 69–85 (2007).

    Article  CAS  Google Scholar 

  2. Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004).

    Article  CAS  Google Scholar 

  3. Babitt, J.L. et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531–539 (2006).

    Article  CAS  Google Scholar 

  4. Goswami, T. & Andrews, N.C. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J. Biol. Chem. 281, 28494–28498 (2006).

    Article  CAS  Google Scholar 

  5. Whitlock, E.P., Garlitz, B.A., Harris, E.L., Beil, T.L. & Smith, P.R. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 145, 209–223 (2006).

    Article  Google Scholar 

  6. Merryweather-Clarke, A.T. et al. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum. Mol. Genet. 12, 2241–2247 (2003).

    Article  CAS  Google Scholar 

  7. Biasiotto, G. et al. Identification of new mutations of hepcidin and hemojuvelin in patients with HFE C282Y allele. Blood Cells Mol. Dis. 33, 338–343 (2004).

    Article  CAS  Google Scholar 

  8. Lee, P.L., Ho, N.J., Olson, R. & Beutler, E. The effect of transferrin polymorphisms on iron metabolism. Blood Cells Mol. Dis. 25, 374–379 (1999).

    Article  CAS  Google Scholar 

  9. Lee, P.L. et al. A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin. Blood Cells Mol. Dis. 27, 783–802 (2001).

    Article  CAS  Google Scholar 

  10. Beutler, E., Gelbart, T. & Lee, P. Haptoglobin polymorphism and iron homeostasis. Clin. Chem. 48, 2232–2235 (2002).

    CAS  Google Scholar 

  11. Lee, P., Gelbart, T., West, C., Halloran, C. & Beutler, E. Seeking candidate mutations that affect iron homeostasis. Blood Cells Mol. Dis. 29, 471–487 (2002).

    Article  CAS  Google Scholar 

  12. Andrews, N.C. Iron homeostasis: insights from genetics and animal models. Nat. Rev. Genet. 1, 208–217 (2000).

    Article  CAS  Google Scholar 

  13. Clothier, B. et al. Genetic variation of basal iron status, ferritin and iron regulatory protein in mice: potential for modulation of oxidative stress. Biochem. Pharmacol. 59, 115–122 (2000).

    Article  CAS  Google Scholar 

  14. LeBoeuf, R.C., Tolson, D. & Heinecke, J.W. Dissociation between tissue iron concentrations and transferrin saturation among inbred mouse strains. J. Lab. Clin. Med. 126, 128–136 (1995).

    CAS  Google Scholar 

  15. Donovan, A. et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 1, 191–200 (2005).

    Article  CAS  Google Scholar 

  16. Grant, G.R. et al. Multiple polymorphic loci determine basal hepatic and splenic iron status in mice. Hepatology 44, 174–185 (2006).

    Article  CAS  Google Scholar 

  17. Muraoka, R.S. et al. The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse. J. Clin. Invest. 103, 1277–1285 (1999).

    Article  CAS  Google Scholar 

  18. Persons, D.A. et al. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nat. Genet. 23, 159–165 (1999).

    Article  CAS  Google Scholar 

  19. Hoffman-Sommer, M., Migdalski, A., Rytka, J. & Kucharczyk, R. Multiple functions of the vacuolar sorting protein Ccz1p in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 329, 197–204 (2005).

    Article  CAS  Google Scholar 

  20. Bonangelino, C.J., Chavez, E.M. & Bonifacino, J.S. Genomic screen for vacuolar protein sorting genes in Saccharomyces cerevisiae. Mol. Biol. Cell 13, 2486–2501 (2002).

    Article  CAS  Google Scholar 

  21. Meiling-Wesse, K. et al. Yeast Mon1p/Aut12p functions in vacuolar fusion of autophagosomes and cvt-vesicles. FEBS Lett. 530, 174–180 (2002).

    Article  CAS  Google Scholar 

  22. Powell, N.D. et al. Cutting edge: macrophage migration inhibitory factor is necessary for progression of experimental autoimmune encephalomyelitis. J. Immunol. 175, 5611–5614 (2005).

    Article  CAS  Google Scholar 

  23. Gu, S., Hu, J., Song, P., Gong, W. & Guo, M. Identification of a new transcript specifically expressed in mouse spermatocytes: mmrp2. Mol. Biol. Rep. 32, 247–255 (2005).

    Article  CAS  Google Scholar 

  24. Levy, J.E., Montross, L.K., Cohen, D.E., Fleming, M.D. & Andrews, N.C. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 94, 9–11 (1999).

    CAS  Google Scholar 

  25. Delaby, C., Pilard, N., Goncalves, A.S., Beaumont, C. & Canonne-Hergaux, F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 106, 3979–3984 (2005).

    Article  CAS  Google Scholar 

  26. Abboud, S. & Haile, D.J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J. Biol. Chem. 275, 19906–19912 (2000).

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations



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.

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Correspondence to Nancy C Andrews.

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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.

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Wang, F., Paradkar, P., Custodio, A. et al. Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice. Nat Genet 39, 1025–1032 (2007).

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