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Abstract

Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor1 is a mode of protein expression highly conserved from protozoa to mammals2. As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells3,4. We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c → g) at position −270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.

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Acknowledgements

We would like to thank D. Araten and R. Notaro for providing the N+ and N− LBCLs; T. Vulliamy and A. Marrone for providing DNA samples and help with the EMSAs, respectively; and I. Dokal, J. Melo, T. Vulliamy, M. Hu and E. Spanoudakis for critical reading of the manuscript. We also thank L. Luzzatto for continuous support and inspiration. A. Almeida is a Leukaemia Research Fund Clinical Research Fellow and A. Karadimitris is a Leukaemia Research Fund Bennett Senior Fellow. T. Kinoshita, Y. Murakami and Y. Maeda are supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Author notes

    • Antonio M Almeida
    •  & Yoshiko Murakami

    These authors contributed equally to this work.

Affiliations

  1. Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12, 0NN, UK.

    • Antonio M Almeida
    • , D Mark Layton
    • , Scott Patterson
    • , Ioannis Kotsianidis
    • , Luigina Mollica
    • , Irene Roberts
    •  & Anastasios Karadimitris
  2. Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565, Japan.

    • Yoshiko Murakami
    • , Yusuke Maeda
    •  & Taroh Kinoshita
  3. Haematological Malignancy Diagnostic Service Laboratory, The Leeds Teaching Hospitals NHS Trust, General Infirmary at Leeds, Great George Street, Leeds, UK.

    • Peter Hillmen
    •  & Stephen Richards
  4. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

    • Gabrielle S Sellick
    •  & Richard Houlston
  5. Clinical and Basic Virology Laboratory, School of Biomedical Sciences, University of Edinburgh, Summerhall, EH9 1HQ, Edinburgh, UK.

    • Dorothy H Crawford
  6. Paediatric Liver Centre, Kings College Hospital, Denmark Hill, SE5 9RS, London, UK.

    • Alastair Baker
  7. Division of Biological Chemistry and Molecular Microbiology, University of Dundee, DD1 4HN, Scotland, UK.

    • Michael Ferguson
  8. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan.

    • Taroh Kinoshita

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Anastasios Karadimitris.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Genome-wide search for the identification of disease gene in inherited GPI deficiency.

  2. 2.

    Supplementary Fig. 2

    GPI expression in the cell lines used in the biochemical experiments.

  3. 3.

    Supplementary Fig. 3

    Restriction enzyme confirmation of the genotypes at position −270.

  4. 4.

    Supplementary Table 1

    Clinical features of children with inherited GPI deficiency.

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DOI

https://doi.org/10.1038/nm1410

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