Lack of the bone morphogenetic protein BMP6 induces massive iron overload (original) (raw)

Nature Genetics volume 41, pages 478–481 (2009)Cite this article

Abstract

Expression of hepcidin, a key regulator of intestinal iron absorption, can be induced in vitro by several bone morphogenetic proteins (BMPs), including BMP2, BMP4 and BMP9 (refs. 1,2). However, in contrast to BMP6, expression of other BMPs is not regulated at the mRNA level by iron in vivo3, and their relevance to iron homeostasis is unclear. We show here that targeted disruption of Bmp6 in mice causes a rapid and massive accumulation of iron in the liver, the acinar cells of the exocrine pancreas, the heart and the renal convoluted tubules. Despite their severe iron overload, the livers of _Bmp6_-deficient mice have low levels of phosphorylated Smad1, Smad5 and Smad8, and these Smads are not significantly translocated to the nucleus. In addition, hepcidin synthesis is markedly reduced. This indicates that Bmp6 is critical for iron homeostasis and that it is functionally nonredundant with other members of the Bmp subfamily. Notably, _Bmp6_-deficient mice retain their capacity to induce hepcidin in response to inflammation. The iron burden in Bmp6 mutant mice is significantly greater than that in mice deficient in the gene associated with classical hemochromatosis (Hfe), suggesting that mutations in BMP6 might cause iron overload in humans with severe juvenile hemochromatosis for which the genetic basis has not yet been characterized.

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Acknowledgements

The authors thank E. Robertson (Dunn School of Pathology, University of Oxford) for kindly providing the _Bmp6_-deficient mice, C. Rouanet for excellent technical assistance, J. Seumois and M. Calise (Service de Zootechnie, IFR30, Toulouse) for their help with the mouse breeding, and S. Allart (Cellular Imaging platform, IFR30), F. Capilla and T. Al Saati (Experimental Histopathology platform, IFR30) for skilled advice. This work was supported in part by grants from the Agence Nationale pour la Recherche (ANR, programme IRONGENES), the European Commission (LSHM-CT-2006-037296: EUROIRON1) and the Fondation pour la Recherche Médicale (to L.K.).

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Author notes

  1. Delphine Meynard and Léon Kautz: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm, U563, Toulouse, F-31300, France
    Delphine Meynard, Léon Kautz, Valérie Darnaud, Hélène Coppin & Marie-Paule Roth
  2. Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan and Institut Biomédical de Toulouse, Toulouse, F-31300, France
    Delphine Meynard, Léon Kautz, Valérie Darnaud, Hélène Coppin & Marie-Paule Roth
  3. Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Gif-sur-Yvette, F-91198, France
    François Canonne-Hergaux

Authors

  1. Delphine Meynard
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  2. Léon Kautz
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  3. Valérie Darnaud
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  4. François Canonne-Hergaux
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  5. Hélène Coppin
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  6. Marie-Paule Roth
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Contributions

D.M., L.K. and V.D. performed phenotype assessment, analyzed data and reviewed the paper; F.C.-H. provided antibodies and technical advice; H.C. and M.-P.R. conceived the project and wrote the manuscript. The last two senior authors contributed equally to the work.

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Correspondence toMarie-Paule Roth.

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Meynard, D., Kautz, L., Darnaud, V. et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload.Nat Genet 41, 478–481 (2009). https://doi.org/10.1038/ng.320

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