Cerebral visual impairment and intellectual disability caused by PGAP1 variants

Abstract

Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI. INTRODUCTIONCerebral visual impairment (CVI) accounts for 27% of the visual impairment in children, and is due to a disorder in projection and/or interpretation of the visual input in the brain. 1-3 Acquired damages, for example, due to preterm birth, are well known causes of CVI, whereas genetic factors are largely unidentified. 4 Several chromosomal aberrations have been associated with CVI, such as Phelan-McDermid syndrome (22q13.3 deletion) and 1p36 microdeletion syndrome. 5 Moreover, single-gene disorders can be implicated in CVI, and, recently, we identified de novo variants in NR2F1 as a cause of CVI. 6 In addition, in several congenital disorders of glycosylation (CDG type 1a, type 1q and type 1v) CVI has been reported. 4,[7][8][9] Glycosylation disorders are caused by a defect in the glycosylation of glycoproteins and glycolipids, and one subclass is the defect in glycosylphosphatidylinositol (GPI) anchor glycosylation. 10 GPI anchor many cell-surface proteins with various functions, so called GPI-anchored proteins (GPI-APs), to the membrane of eukaryotic cells. 11-13 GPI is synthesized in the endoplasmic reticulum, transferred to the proteins, and remodeled. During the biosynthesis of GPI anchors, an acyl chain is linked to the inositol. This acyl chain is a transient structure and is necessary for efficient completion of later steps in GPI biosynthesis. After the attachment of GPI to the protein, this acyl chain is removed by PGAP1 (post-GPI attachment to proteins 1), the first step of the remodeling phase. 14 Subsequently, the GPI anchor is transported from the endoplasmic reticulum to the plasma membrane through the Golgi apparatus and further remodeled. When the inositol-linked...

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

“…Only three patients had epilepsy, which was surprising considering almost all patients with mutations in other genes of the GPI biosynthesis pathway suffered from seizures, with the exception of patients with PGAP2 mutations where less than half of the patients were affected. Furthermore, only a minority of patients had facial dysmorphism which was also unexpected as dysmorphic features were known as a common phenotype in patients with GPI disorders …”

Novel genetic causes for cerebral visual impairment

“…The third glycosylation gene in which a variant was identified, PGAP1 (patient 12, reported elsewhere), is important in the GPI-anchor synthesis pathway. 26 Several other genes, PIGA, PIGN, and PIGT, implicated in this pathway are known to be implicated in CVI and ID as well, 29,[37][38][39][40] and recently, also PGAP1 variants were found to be associated with CVI and ID. 29,41 RERE is another gene with a functional link with a gene known to be aberrant in CVI.…”

“…Pictures of patients 12, 13, and 23 have previously been published. 13,26 DISCUSSION WES was performed in 25 patients with CVI and a visual acuity of ≤ 0.3, without acquired risk factors for CVI nor pathogenic copy number variants. We identified variants in four known CVI-associated genes, namely AHDC1, NGLY1, NR2F1, and PGAP1, and 19 candidate genes for CVI.…”

“…Three patients (12, 13, and 23) were part of previous reports. 13,26 The variants identified have been submitted to the Leiden Open Variation Databases (LOVDs) (http://databases. lovd.nl/, patient IDs #00025011 and #00039389-#000394012).…”

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

“…Both of the affected individuals had intellectual disability and encephalopathy ( 125 ). Biallelic PGAP1 mutations, p.Pro92del and Lys308Asnfs*25, were found in a boy with cerebral visual impairment and intellectual disability ( 126 ). Another set of biallelic PGAP1 mutations, p.Gln466* and p.Tyr524*, were found in a boy with cerebral visual impairment, hypotonia, delayed motor development, and encephalopathy ( 127 ).…”