Cerebral visual impairment and intellectual disability caused by PGAP1 variants.

TitleCerebral visual impairment and intellectual disability caused by PGAP1 variants.
Publication TypeJournal Article
Year of Publication2015
AuthorsBosch, DGM, F Boonstra, N, Kinoshita, T, Jhangiani, S, de Ligt, J, Cremers, FPM, Lupski, JR, Murakami, Y, de Vries, BBA
JournalEur J Hum Genet
Date Published2015 Dec
KeywordsAnimals, Cell Line, Tumor, Child, CHO Cells, Cricetinae, Cricetulus, Humans, Intellectual Disability, Male, Membrane Proteins, Mutation, Phosphoinositide Phospholipase C, Phosphoric Monoester Hydrolases, Syndrome, Vision Disorders, Visual Perception

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.

Alternate JournalEur J Hum Genet
PubMed ID25804403
PubMed Central IDPMC4795198
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States

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