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

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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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Figure 1: Schematic representation of TMPRSS6 mutations and corresponding TMPRSS6 domains.

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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.).

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Author notes

  1. Karin E Finberg & Nancy C Andrews

    Present address: 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.),

  2. Matthew M Heeney and Dean R Campagna: These authors contributed equally to this work.

  3. Nancy C Andrews and Mark D Fleming: These authors contributed equally to this work.

Authors and Affiliations

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

    Karin E Finberg

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

    Karin E Finberg, Matthew M Heeney & Nancy C Andrews

  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Matthew M Heeney

  4. Department of Pathology, Children's Hospital Boston, Boston, 02115, Massachusetts, USA

    Dean R Campagna & Mark D Fleming

  5. Department of Pediatric Hematology, Ege University Faculty of Medicine, Bornova, 35100, Izmir, Turkey

    Yeşim Aydınok

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

    Howard A Pearson

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

    Kip R Hartman

  8. Department of Pathology, Saint Louis University School of Medicine, St. Louis, 63104, Missouri, 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, 21205, Maryland, USA

    John J Strouse

  11. Program in Genomics, Children's Hospital Boston, Boston, 02115, Massachusetts, USA

    Kyriacos Markianos

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

    Kyriacos Markianos & Nancy C Andrews

  13. Department of Pathology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mark D Fleming

Authors
  1. Karin E Finberg
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  2. Matthew M Heeney
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  3. Dean R Campagna
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  4. Yeşim Aydınok
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  5. Howard A Pearson
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  6. Kip R Hartman
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  7. Mary M Mayo
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  8. Stewart M Samuel
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  9. John J Strouse
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  10. Kyriacos Markianos
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  11. Nancy C Andrews
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  12. 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

Supplementary Text and Figures

Supplementary Note, Supplementary Methods, Supplementary Tables 1 and 2, Supplementary Figures 1–3 (PDF 1142 kb)

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Finberg, K., Heeney, M., Campagna, D. et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 40, 569–571 (2008). https://doi.org/10.1038/ng.130

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

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