Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia

Abstract

Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors >150 various proteins to the cell surface. At least 27 genes are involved in biosynthesis and transport of GPI-anchored proteins (GPI-APs). To date, mutations in 13 of these genes are known to cause inherited GPI deficiencies (IGDs), and all are inherited as recessive traits. IGDs mainly manifest as intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms are caused by the decreased surface expression of GPI-APs or by structural abnormalities of GPI. Here, we present five affected individuals (from two consanguineous families from Egypt and Pakistan and one non-consanguineous family from Japan) who show intellectual disability, hypotonia, and early-onset seizures. We identified pathogenic variants in PIGG, a gene in the GPI pathway. In the consanguineous families, homozygous variants c.928C>T (p.Gln310(∗)) and c.2261+1G>C were found, whereas the Japanese individual was compound heterozygous for c.2005C>T (p.Arg669Cys) and a 2.4 Mb deletion involving PIGG. PIGG is the enzyme that modifies the second mannose with ethanolamine phosphate, which is removed soon after GPI is attached to the protein. Physiological significance of this transient modification has been unclear. Using B lymphoblasts from affected individuals of the Egyptian and Japanese families, we revealed that PIGG activity was almost completely abolished; however, the GPI-APs had normal surface levels and normal structure, indicating that the pathogenesis of PIGG deficiency is not yet fully understood. The discovery of pathogenic variants in PIGG expands the spectrum of IGDs and further enhances our understanding of this etiopathogenic class of intellectual disability.

PGAP3‐related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation

“…They are caused by mutations in 2 different classes of genes: PIG (phosphatidylinositol glycan) involved in the biosynthesis and transfer of GPI while PGAP (post GPI attachment to proteins) incorporated in structural remodeling of GPI after its attachment to proteins. About 27 PIG and PGAP genes are engaged in the GPI‐anchor biosynthesis, transport and remodeling pathway . Mutations in more than 13 PIG and PGAP genes have been described to cause inherited GPI deficiencies.…”

Inherited glycophosphatidylinositol deficiency variant database and analysis of pathogenic variants

“…In the case of PIGG , the affected patient had severe developmental delay, but the authors discovered, through functional analysis, that the deletion of the whole gene does not cause decreased expression of GPI‐APs at the cell surface nor an impaired GPI‐AP structure. This is explained by the role of the PIGG protein during biosynthesis: in normal cells, PIGG transfers an EtNP to the second mannose of the GPI‐anchor, but this side chain is eventually removed by the PGAP5 protein later in the process (Makrythanasis et al, ).…”

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

“…Also, at least three splicing defective variants of PGAP1 (MIM 611655) have been reported in autosomal recessive mental retardation‐42 (MRT42, MIM 615802) and related syndromes with psychomotor retardation and brain atrophy as well as other features (Granzow et al., ; Kettwig et al., ; Novarino et al., ). More IGD cases with splicing defective variants include one variant of PGAP3 (MIM 611801) in hyperphosphatasia with mental retardation syndrome 4 (HPMRS4, MIM 615716) (Knaus et al., ), two variants of PIGL (MIM 605947) in Chime syndrome (MIM 280000) and related neurodevelopmental disorder (Ng et al., ; Pagnamenta et al., ), one variant of PIGO (MIM 614730) in HPMRS2 (MIM 614749) (Krawitz et al., ), and one variant of PIGG (MIM 616918) in autosomal recessive mental retardation‐53 (MRT53, MIM 616917) (Makrythanasis et al., ), etc . Therefore, it is not quite surprising that a putative splicing defective variant was uncovered in PIGA gene under a disease condition.…”