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

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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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.

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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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