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Eur J Hum Genet. 2015 Dec;23(12):1689-93. doi: 10.1038/ejhg.2015.42. Epub 2015 Mar 25.

Cerebral visual impairment and intellectual disability caused by PGAP1 variants.

Author information

1
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
2
Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands.
3
Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
4
Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Research Institute for Microbial Diseases and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
6
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
8
Texas Children's Hospital, Houston, TX, USA.
9
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

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.

PMID:
25804403
PMCID:
PMC4795198
DOI:
10.1038/ejhg.2015.42
[Indexed for MEDLINE]
Free PMC Article

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