2. Academic Validation
  3. Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy

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

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.

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