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Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency

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Abstract

The congenital form of thrombotic thrombocytopenic purpura (TTP) is caused by genetic mutations in ADAMTS13. Some, but not all, congenital TTP patients manifest renal insufficiency in addition to microangiopathic hemolysis and thrombocytopenia. We included 32 congenital TTP patients in the present study, which was designed to assess whether congenital TTP patients with renal insufficiency have predisposing mutations in complement regulatory genes, as found in many patients with atypical hemolytic uremic syndrome (aHUS). In 13 patients with severe renal insufficiency, six candidate complement or complement regulatory genes were sequenced and 11 missense mutations were identified. One of these missense mutations, C3:p.K155Q mutation, is a rare mutation located in the macroglobulin-like 2 domain of C3, where other mutations predisposing for aHUS cluster. Several of the common missense mutations identified in our study have been reported to increase disease-risk for aHUS, but were not more common in patients with as compared to those without renal insufficiency. Taken together, our results show that the majority of the congenital TTP patients with renal insufficiency studied do not carry rare genetic mutations in complement or complement regulatory genes.

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Acknowledgments

This work was supported in part by grants-in-aid from the Ministry of Health, Labor, and Welfare of Japan, the Japan Society for the Promotion of Science, the Takeda Science Foundation and the Swiss National Science Foundation (Grant Nr 32003B-124892 and 310030-160269). The hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov identifier NCT01257269) is supported by an investigator initiated research grant from Baxter Bioscience. The research activity of Dr. Fan was supported by a Scholarship from the Takeda Science Foundation. Dr. Eura was a recipient of a scholarship from the Association for Preventive Medicine of Japan.

Author information

Authors and Affiliations

  1. Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan

    Xinping Fan, Hiroko Shirotani-Ikejima, Yuka Eura, Hidenori Hirai, Shigenori Honda, Koichi Kokame & Toshiyuki Miyata

  2. Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland

    Johanna A. Kremer Hovinga, Magnus Mansouri Taleghani & Bernhard Lämmle

  3. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    Anne-Sophie von Krogh

  4. Department of Hematology, St Olavs Hospital Trondheim University Hospital, Trondheim, Norway

    Anne-Sophie von Krogh

  5. Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan

    Yoko Yoshida & Yoshihiro Fujimura

  6. Department of Clinical Laboratory, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

    Xinping Fan

  7. Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

    Bernhard Lämmle

  8. Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan

    Toshiyuki Miyata

Authors
  1. Xinping Fan
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  2. Johanna A. Kremer Hovinga
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  6. Shigenori Honda
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  7. Koichi Kokame
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  8. Magnus Mansouri Taleghani
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  9. Anne-Sophie von Krogh
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  10. Yoko Yoshida
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  11. Yoshihiro Fujimura
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  13. Toshiyuki Miyata
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Corresponding authors

Correspondence to Johanna A. Kremer Hovinga or Toshiyuki Miyata.

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Conflict of interest

Dr. Lämmle is a member of the Data Safety Monitoring committee of the BAX 930 Study testing rADAMTS13 in congenital TTP patients. Dr. Fujimura is a recipient of the research fund from Alexion Pharmaceuticals. Other authors have no conflict of interests.

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Fan, X., Kremer Hovinga, J.A., Shirotani-Ikejima, H. et al. Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency. Int J Hematol 103, 283–291 (2016). https://doi.org/10.1007/s12185-015-1933-7

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  • DOI: https://doi.org/10.1007/s12185-015-1933-7

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