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Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)

Nature Genetics volume 40, pages 569571 (2008) | Download Citation

Abstract

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

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Acknowledgements

We thank the families for their invaluable contribution to this study. We are indebted to E. Neufeld for ongoing mentorship. We thank C. Trenor, A. Donovan, I. Rubio-Aliaga and other members of the Andrews laboratory for their contributions to the early stages of this project. We thank A.J. Iafrate and J. Miller for technical advice and assistance. K.E.F. was supported by T32 CA009216 awarded to the Department of Pathology, Massachusetts General Hospital. This work was also supported by R01 DK080011 (M.D.F.), K12 HL087164 (M.M.H.), R01 DK066373 (N.C.A.) and DK053813 (N.C.A.).

Author information

Author notes

    • Karin E Finberg
    •  & Nancy C Andrews

    Present addresses: Department of Pathology, Duke University School of Medicine, Durham, North Carolina 27710, USA (K.E.F.) and Department of Pediatrics and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA (N.C.A.)

    • Matthew M Heeney
    •  & Dean R Campagna

    These authors contributed equally to this work.

    • Nancy C Andrews
    •  & Mark D Fleming

    These authors contributed equally to this work.

Affiliations

  1. Pathology Service, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Karin E Finberg
  2. Division of Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

    • Karin E Finberg
    • , Matthew M Heeney
    •  & Nancy C Andrews
  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • Matthew M Heeney
  4. Department of Pathology, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

    • Dean R Campagna
    •  & Mark D Fleming
  5. Department of Pediatric Hematology, Ege University Faculty of Medicine, 35100 Bornova, Izmir, Turkey.

    • Yeşim Aydınok
  6. Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut 06520, USA.

    • Howard A Pearson
  7. Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.

    • Kip R Hartman
  8. Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.

    • Mary M Mayo
  9. Pediatric Health Associates, P.C., Plainview, New York 11803, USA.

    • Stewart M Samuel
  10. Division of Pediatric Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    • John J Strouse
  11. Program in Genomics, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

    • Kyriacos Markianos
  12. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Kyriacos Markianos
    •  & Nancy C Andrews
  13. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Mark D Fleming

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Contributions

K.E.F. obtained institutional review board approval and consents, designed, conducted and interpreted results from the segregation studies and sequence analysis, and prepared the manuscript. M.M.H. obtained institutional review board approval and consents and coordinated clinical sample acquisition and clinical data analysis. D.R.C. conducted and interpreted results from the sequencing analysis and assisted with the segregation studies and other technical aspects of the project. Y.A., H.A.P., K.R.H., M.M.M. S.M.S. and J.J.S. were clinical collaborators who provided samples from affected individuals, phenotypic information and results of laboratory testing. K.M. interpreted results from the segregation studies and sequencing analysis. N.C.A. and M.D.F. obtained institutional review board approval and consents, supervised the design of experiments and data interpretation, and prepared the manuscript. N.C.A. also provided samples from affected individuals, phenotypic information and results of laboratory testing.

Note: Supplementary information is available on the Nature Genetics website.

Corresponding authors

Correspondence to Nancy C Andrews or Mark D Fleming.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Methods, Supplementary Tables 1 and 2, Supplementary Figures 1–3

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DOI

https://doi.org/10.1038/ng.130

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