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Paroxysmal Nocturnal Hemoglobinuria pp 11–54Cite as

Synthesis, Genetics, and Congenital Diseases of GPI-Anchored Proteins

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Abstract

In this chapter, we present basic research covering paroxysmal nocturnal hemoglobinuria (PNH). PNH is characterized by impaired regulation of the complement system because of reduced surface expression of complement regulatory molecules, CD55 (DAF) and CD59. Both proteins are glycosylphosphatidylinositol-anchored proteins (GPI-APs) present in wide variety of cells exposed to complement. GPI-AP deficiency is caused by somatic mutation of PIGA in hematopoietic stem cells, the primary defect in PNH. Clinical manifestations, such as hemolytic anemia, also occur when other factors induce clonal expansion of the affected hematopoietic stem cells. Although a defect in any 20 or more genes essential for GPI biosynthesis and/or remodeling can cause PNH, only PIGA, encoding an enzyme catalyzing the first step in GPI biosynthesis, was known to be a gene responsible for PNH over the last two decades. This is because among the more than 20 genes, PIGA is the only gene located on the X-chromosome and a single mutation is sufficient to cause PIG-A dysfunction. PNH caused by compound defects of somatic and germ line mutations in the PIGT gene located on chromosome 20 was recently found. In addition to PNH, revolutionary development of next-generation sequencing (NGS) has enabled the identification of inherited GPI deficiencies with various clinical phenotypes, such as intellectual disability, developmental delay, seizures, and hypotonia. Currently, individuals with mutations in 12 genes along the GPI biosynthetic pathway have been identified. Further development of NGS will facilitate discovery of more inherited GPI deficiencies and possibly PNH. Therefore, characterizing the biosynthetic pathway of GPI is increasingly more important for understanding the pathology of GPI deficiencies.

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Authors and Affiliations

  1. Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yusuke Maeda & Yoshiko Murakami M.D., Ph.D.

  2. Department of Immunoglycobiology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yusuke Maeda & Yoshiko Murakami M.D., Ph.D.

  3. Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Taroh Kinoshita

  4. WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Taroh Kinoshita

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  1. Yusuke Maeda
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  2. Yoshiko Murakami M.D., Ph.D.
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  3. Taroh Kinoshita
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Correspondence to Yusuke Maeda .

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  1. Department of Hematology and Ocology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Yuzuru Kanakura

  2. Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan

    Taroh Kinoshita

  3. Dept of Hematology and Ocology, Osaka University Dept of Hematology and Ocology, Suita, Osaka, Japan

    Jun-ichi Nishimura

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Maeda, Y., Murakami, Y., Kinoshita, T. (2017). Synthesis, Genetics, and Congenital Diseases of GPI-Anchored Proteins. In: Kanakura, Y., Kinoshita, T., Nishimura, Ji. (eds) Paroxysmal Nocturnal Hemoglobinuria. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56003-6_2

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