Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy
Devon L Johnstone1, Thi-Tuyet-Mai Nguyen2, Yoshiko Murakami3
1Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
Insights
Mutations in the PIGP gene cause a novel inherited GPI deficiency (IGD). This condition leads to severe developmental disorders, including seizures and hypotonia, impacting cell surface protein function.
Area of Science:
- Biochemistry
- Genetics
- Developmental Biology
Background:
- Glycosylphosphatidylinositol (GPI) anchors attach over 150 human proteins to the cell surface, crucial for development, especially neurogenesis.
- Mutations in GPI anchor biosynthesis disrupt these functions, leading to inherited GPI deficiencies (IGDs), a class of congenital disorders of glycosylation.
Observation:
- Two siblings presented with compound heterozygous variants in the PIGP gene, encoding a key enzyme in GPI anchor biosynthesis.
- Clinical presentation included early-onset refractory seizures, hypotonia, and profound global developmental delay, characteristic of IGD phenotypes.
Findings:
- Patient cells exhibited reduced PIGP mRNA levels and a consequent decrease in cell surface GPI-anchored proteins.
- Functional rescue was achieved by introducing wild-type PIGP, confirming the pathogenicity of the identified variants.
Implications:
- This study identifies mutations in PIGP as a cause of a novel autosomal recessive inherited GPI deficiency.
- Expands understanding of PIG genes' critical roles in human development and neurogenesis.
- Highlights the importance of GPI anchor pathway integrity for normal development.
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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