|Title||Cerebral visual impairment and intellectual disability caused by PGAP1 variants.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Bosch, DGM, F Boonstra, N, Kinoshita, T, Jhangiani, S, de Ligt, J, Cremers, FPM, Lupski, JR, Murakami, Y, de Vries, BBA|
|Journal||Eur J Hum Genet|
|Date Published||2015 Dec|
|Keywords||Animals, 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 Journal||Eur. J. Hum. Genet.|
|PubMed Central ID||PMC4795198|
|Grant List||U54 HG006542 / HG / NHGRI NIH HHS / United States |
U54HG006542 / HG / NHGRI NIH HHS / United States
Cerebral visual impairment and intellectual disability caused by PGAP1 variants.
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