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.

Figure 1

Phenotype of the affected individual and the functional analysis of the variants. (a) Photographs of the affected individual, note the upward slanting palpebral fissures, deep-set eyes, large ear lobes and prominent helices and antihelices. (b) Schematic representation of PGAP1-containing transmembrane domains (in green). The positions of the variants identified in this study and in the previous reports are indicated. ^†For this variant the effect on amino acid sequence was not studied. ^††Considered as a variant without functional impact. (c) CHO cells deficient for PGAP1 were used to investigate the expected structural abnormalities of the GPI anchors by testing the sensitivity of GPI-APs to PI-PLC. Wild-type PGAP1 and the construct containing the variant c.914C>T (p.(Ala305Val)) rescued the sensitivity for PI-PLC strongly suggesting that this variant is benign. The PGAP1 constructs containing the c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)) variants did not increase the sensitivity for PI-PLC, suggesting that both are causal.