Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases

Yoshiko Murakami, Thi Tuyet Mai Nguyen, Nissan Baratang, Praveen K. Raju, Alexej Knaus, Sian Ellard, Gabriela Jones, B. Lace, Justine Rousseau, Norbert Fonya Ajeawung, Atsushi Kamei, Gaku Minase, Manami Akasaka, Nami Araya, E. Koshimizu, Jenneke van den Ende, Florian Erger, Janine Altmüller, Zita Krumina, Jurgis StrautmanisInna Inashkina, J. Stavusis, A. El-Gharbawy, Jessica Sebastian, Ratna Dua Puri, Samarth Kulshrestha, Ishwar C. Verma, Esther M. Maier, Tobias B. Haack, Anil Israni, J. Baptista, Adam Gunning, Jill A. Rosenfeld, Pengfei Liu, Marieke Joosten, María Eugenia Rocha, Mais O. Hashem, Hesham M. Aldhalaan, Fowzan S. Alkuraya, Satoko Miyatake, Naomichi Matsumoto, Peter M. Krawitz, Elsa Rossignol, T. Kinoshita, Philippe M. Campeau

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.

Original languageEnglish
Pages (from-to)384-394
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 1 Aug 2019


  • alkaline phosphatase
  • DOORS syndrome
  • epilepsy
  • glycosylphosphatidylinositol
  • inherited GPI deficiency (IGD)
  • intellectual disability
  • neuropathy
  • PIGB
  • seizures

Field of Science*

  • 3.1 Basic medicine
  • 3.2 Clinical medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database


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