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Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability
  1. Simon Edvardson1,2,
  2. Yoshiko Murakami3,
  3. Thi Tuyet Mai Nguyen4,
  4. Maher Shahrour5,
  5. Anik St-Denis6,
  6. Avraham Shaag1,
  7. Nadira Damseh5,
  8. Françoise Le Deist4,6,7,8,
  9. Yenan Bryceson9,
  10. Bassam Abu-Libdeh5,
  11. Philippe M Campeau4,8,
  12. Taroh Kinoshita3,
  13. Orly Elpeleg1
  1. 1Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  2. 2Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  3. 3WPI Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
  4. 4CHU Sainte-Justine Research Center, University of Montreal, Montreal, Québec, Canada
  5. 5Department of Pediatrics and Genetics, Makassed Hospital, Al-Quds Medical School, Jerusalem, Israel
  6. 6Department of Microbiology and Immunology, CHU Sainte Justine, Montreal, Québec, Canada
  7. 7Department of Microbiology Infectiology and Immunology, University of Montreal, Montreal, Québec, Canada
  8. 8Department of Pediatrics, University of Montreal, Montreal, Québec, Canada
  9. 9Department of Medicine, Centre for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
  1. Correspondence to Professor Orly Elpeleg, Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Elpeleg{at}hadassah.org.il

Abstract

Background Of our 1400 exome-studied patients, 67% originate from consanguineous families. ∼80% suffer from variable degree of intellectual disability (ID). The search for disease causing genes using homozygosity mapping was progressing slowly until 2010, then markedly accelerated by the introduction of exome analysis.

Objectives To identify the disease causing mutation(s) in three patients from two unrelated families who suffered from global developmental delay, severe ID and drug-responsive seizure disorder.

Methods Exome analysis was performed in DNA of the three patients. The identified PIGC variants were generated and transfected into PIGC-defective mouse cells and the restoration of the surface expression of mouse CD90, CD48 and FLAER was assessed using flow cytometry. The expression of these proteins was also studied on the surface of patients' leucocytes.

Results Three PIGC mutations were identified; homozygous p.L189W in one family and compound heterozygosity for p.L212P/p.R21X variants in another. PIGC participates in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor which tethers proteins to plasma membrane. In cells lacking PIGC protein, which were transfected with each of the PIGC variants, we detected a clear reduction of surface expression of GPI-anchored proteins. Furthermore, analyses of patients' leucocytes showed significant and constant decrease of CD16 surface expression in granulocytes, and moderate decrease of CD14, CD55, CD59 and FLAER levels.

Conclusions PIGC joins the list of genes in which mutations result in defective biosynthesis of GPI anchoring, manifesting by global developmental delay and seizure disorder. The lack of specific biomarker dictates exome sequencing as the diagnostic procedure of choice in similar patients.

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