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.
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Acknowledgements
We are grateful to the individual involved and his family for their support and cooperation. We thank the technical ophthalmological assistant P. Rison for his assistance during the ophthalmological examination. This work has been supported by grants from Stichting ODAS (to FNB and FPMC), Vereniging Bartiméus-Sonneheerdt (5781251 to FNB and FPMC), and the Dutch Organization for Health Research and Development (917-86-319 and 912-12-109 to BBAdV). In addition, this study was accomplished in part through the Center for Mendelian Genomics research effort funded by the National Institutes of Health and supported by the National Human Genome Research Institute grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics.
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Bosch, D., Boonstra, F., Kinoshita, T. et al. Cerebral visual impairment and intellectual disability caused by PGAP1 variants. Eur J Hum Genet 23, 1689–1693 (2015). https://doi.org/10.1038/ejhg.2015.42
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DOI: https://doi.org/10.1038/ejhg.2015.42
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