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.

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