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Case Reports
. 2017 May 1;26(9):1706-1715.
doi: 10.1093/hmg/ddx077.

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

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
Case Reports

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

Devon L Johnstone et al. Hum Mol Genet. .

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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