title: 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.
authors: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Daniëlle G M
authors: DG
authors: Bosch
authors: Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands.|Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: F Nienke
authors: FN
authors: Boonstra
authors: Research Institute for Microbial Diseases and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors: Taroh
authors: T
authors: Kinoshita
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors: Shalini
authors: S
authors: Jhangiani
authors: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Joep
authors: J
authors: de Ligt
authors: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Frans P M
authors: FP
authors: Cremers
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Texas Children's Hospital, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors: James R
authors: JR
authors: Lupski
authors: Research Institute for Microbial Diseases and WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors: Yoshiko
authors: Y
authors: Murakami
authors: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Bert B A
authors: BB
authors: de Vries
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002648:Child; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D014786:Vision Disorders / Q000175:diagnosis / Q000235:genetics*; D014796:Visual Perception
chemical_list: D008565:Membrane Proteins; C484857:PGAP1 protein, human; D010744:Phosphoric Monoester Hydrolases; D054801:Phosphoinositide Phospholipase C