Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy

  • Hum Mol Genet. 2017 May 1;26(9):1706-1715. doi: 10.1093/hmg/ddx077.
Devon L Johnstone  1 ,  Thi-Tuyet-Mai Nguyen  2 ,  Yoshiko Murakami  3 ,  Kristin D Kernohan  1 ,  Martine Tétreault  4  5 ,  Claire Goldsmith  6 ,  Asif Doja  7 ,  Justin D Wagner  1 ,  Lijia Huang  1 ,  Taila Hartley  1 ,  Anik St-Denis  2 ,  Françoise le Deist  2 ,  Jacek Majewski  4  5 ,  Dennis E Bulman  1 ,  Care4Rare Canada Consortium ,  Taroh Kinoshita  3 ,  David A Dyment  1  6 ,  Kym M Boycott  1  6 ,  Philippe M Campeau  2  8
Affiliations
  • 1. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
  • 2. Research Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec H3T1C5, Canada.
  • 3. WPI Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 4. Department of Human Genetics, McGill University, Montreal, Quebec H3A1B1, Canada.
  • 5. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A0G1, Canada.
  • 6. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H8L1, Canada.
  • 7. Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H8L1, Canada.
  • 8. Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec H3T1C5, Canada.
PMID: 28334793 DOI: 10.1093/hmg/ddx077
Abstract

There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability. Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis. Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of Other IGD phenotypes. Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development.