ArticleAmerican journal of human genetics2013
Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability.
Article in American journal of human genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers, 2 of them syntheses that pooled it.
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Who cites it
61 citing papers in PubMed, 2 syntheses or guidelines pooled it, 98 citations in OpenAlex.
- Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review.Frontiers in neurology · 2021Pooled it
- Mapping the Diverse Genetic Disorders and Rare Diseases Among the Syrian Population: Implications on Refugee Health and Health Services in Host Countries.Journal of immigrant and minority health · 2020Pooled it
- Expanding the genotypic and phenotypic spectrum of PGAP1 deficiency: clinical and functional insights from 15 patients.European journal of human genetics : EJHG · 2026Article
- Genetic dissection of the role ofiScience · 2026Article
- Reporting a Novel Disease Causing Variant in PGAP3 Associated With Hyperphosphatasia and Intellectual Disability: A Case Report and Comprehensive Literature Review.Molecular genetics & genomic medicine · 2026Review
- Gene replacement therapy for Piga GPI-anchor deficiency in the developing nervous system.bioRxiv : the preprint server for biology · 2025Article
- Homozygous PGAP2 Mutation Causes Hyperphosphatasia with Mental Retardation Syndrome-3: Genetic and Clinical Evaluation of the Ultra-Rare Inherited Glycosylphosphatidylinositol Biosynthesis Defect.Molecular syndromology · 2025Article
- A Novel Homozygous Missense Variant ofInternational journal of molecular sciences · 2025Article
- Article
- The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.Brain : a journal of neurology · 2024Observational
- Article
- A case report ofFrontiers in pediatrics · 2024Article
- Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum ofHuman mutation · 2024Article
- Excluding Digenic Inheritance ofGenes · 2023Article
- Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid.JIMD reports · 2023Article
- Article
- C18orf32 loss-of-function is associated with a neurodevelopmental disorder with hypotonia and contractures.Human genetics · 2022Article
- Genome-wide screening of sex-biased genetic variants potentially associated with COVID-19 hospitalization.Frontiers in genetics · 2022Article
- Biosynthesis and biology of mammalian GPI-anchored proteins.Open biology · 2020Review
- Case Report: Compound Heterozygous Phosphatidylinositol-Glycan Biosynthesis Class N (Frontiers in genetics · 2020Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain.
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