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Growth differentiation factor 15 in patients with congenital dyserythropoietic anaemia (CDA) type II

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Abstract

Congenital dyserythropoietic anaemias (CDAs) are heterogeneous, hereditary disorders hallmarked by ineffective erythropoiesis and tissue iron overload. Growth differentiation factor 15 (GDF15) was suggested to mediate iron overload in iron-loading anaemias, such as the thalassaemias and CDAI by suppressing hepcidin, the key regulator of iron absorption. Here, we show that serum GDF15 concentrations are elevated in subjects with CDAI and CDAII. Despite similar disease characteristics, CDAI patients present with significantly higher GDF15 concentrations compared to CDAII patients. Hepcidin concentrations are inappropriately low in CDAII patients considering the severe hepatic iron overload associated with this disorder. GDF15 significantly correlates with the degree of anaemia (Hb), the response of erythropoiesis (reticulocyte index) as well as with iron availability in the serum (transferrin saturation). The observation that GDF15 is elevated in CDAII patients is consistent with the proposal that GDF15 is among the erythroid factors down-regulating hepcidin and contributing to iron overload in conditions of dyserythropoiesis.

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Acknowledgements

We thank Rosi Leichtle (Department for Internal Medicine III, University Hospital of Ulm) for the collection of patient samples, and Raeka S. Aiyar and Julien Gagneur for their useful advice during the analysis of the data. M.U.M. acknowledges funding from the E-RARE/BMBF project 01GM1005.

Conflicts of interest

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Department of Paediatric Oncology, Haematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 153, 69120, Heidelberg, Germany

    Guillem Casanovas, Sandro Altamura & Martina U. Muckenthaler

  2. Molecular Medicine Partnership Unit, Heidelberg, Germany

    Guillem Casanovas, Sandro Altamura & Martina U. Muckenthaler

  3. European Molecular Biology Laboratory, Heidelberg, Germany

    Guillem Casanovas

  4. Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

    Dorine W. Swinkels & Coby M. Laarakkers

  5. Institute for Transfusion Medicine, University of Ulm, Ulm, Germany

    Klaus Schwarz & Markus Wiesneth

  6. Institute for Clinical Transfusion Medicine and Immunogenetics, Ulm, German Red Cross, Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany

    Klaus Schwarz & Markus Wiesneth

  7. Central Laboratory of University Hospitals, Ulm, Germany

    Hans-Juergen Gross

  8. Department of Internal Medicine III, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany

    Hermann Heimpel

Authors
  1. Guillem Casanovas
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  2. Dorine W. Swinkels
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  3. Sandro Altamura
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  4. Klaus Schwarz
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  5. Coby M. Laarakkers
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  6. Hans-Juergen Gross
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  7. Markus Wiesneth
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  8. Hermann Heimpel
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  9. Martina U. Muckenthaler
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Corresponding authors

Correspondence to Hermann Heimpel or Martina U. Muckenthaler.

Additional information

G. Casanovas and D. W. Swinkels contributed equally to this work.

H. Heimpel and M. U. Muckenthaler contributed equally to this work.

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Supplementary Fig. 1

Soluble transferrin receptor correlations in CDAII patients. Correlations of soluble transferrin receptor with (A) ferritin, (B) the hepcidin to ferritin ratio and (C) hepcidin in CDAII patients (n = 23). Correlations are shown on a logarithmic scale, with the statistical values (ρ and P) indicated. Trend lines are based on the logarithms of the values. (JPEG 218 kb)

High-resolution image (EPS 2541 kb)

Supplementary Table 1

Serum parameters tested in healthy volunteers (1–39) and unaffected family members of CDA patients (40–48). *NA not available (PDF 65 kb)

Supplementary Table 2

Representative blood parameters tested in CDAI and CDAII patients. (*) History of splenectomy; (**) iron depletion; (***) regular transfusions. NA not available (PDF 69 kb)

Supplementary Table 3

Blood parameters tested in samples from CDAI and CDAII patients. (*) History of splenectomy; (**) receiving iron depletion; (***) regular transfusions. NA not available (PDF 73 kb)

Supplementary Table 4

Serum parameters in healthy controls, CDAI and CDAII patients. Mean values and rank (highest and lowest value) are shown. Statistical significance was calculated by a nonparametric Mann–Whitney test. * (number of men/number of women); NS not significant; † reference values are shown for controls (measurements not available). (PDF 57 kb)

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Casanovas, G., Swinkels, D.W., Altamura, S. et al. Growth differentiation factor 15 in patients with congenital dyserythropoietic anaemia (CDA) type II. J Mol Med 89, 811–816 (2011). https://doi.org/10.1007/s00109-011-0751-5

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  • DOI: https://doi.org/10.1007/s00109-011-0751-5

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