ArticleHuman molecular genetics2020
CNS glycosylphosphatidylinositol deficiency results in delayed white matter development, ataxia and premature death in a novel mouse model.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 23 citations in OpenAlex.
- A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG.PLoS genetics · 2026Article
- Genetic dissection of the role ofiScience · 2026Article
- A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG.bioRxiv : the preprint server for biology · 2026Article
- Gene replacement therapy for Piga GPI-anchor deficiency in the developing nervous system.bioRxiv : the preprint server for biology · 2025Article
- Identification of CNTN2 as a genetic modifier of PIGA-CDG in a family with incomplete penetrance and in Drosophila.American journal of human genetics · 2025Article
- SMPD4-mediated sphingolipid metabolism regulates brain and primary cilia development.Development (Cambridge, England) · 2024Article
- PIGK defects induce apoptosis in Purkinje cells and acceleration of neuroectodermal differentiation.Cell death & disease · 2024Article
- The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.Brain : a journal of neurology · 2024Observational
- Promise of gene therapy for congenital neurologic disease due to GPI deficiency.Molecular therapy. Methods & clinical development · 2024Article
- AAV-based gene therapy ameliorated CNS-specific GPI defect in mouse models.Molecular therapy. Methods & clinical development · 2024Article
- Drosophila models of phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) mirror patient phenotypes.G3 (Bethesda, Md.) · 2024Article
- A Novel HomozygousGenes · 2023Article
- The Regulatory Roles of Cerebellar Glycosphingolipid Microdomains/Lipid Rafts.International journal of molecular sciences · 2023Review
- Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions.NPJ Parkinson's disease · 2022Article
- Establishment of mouse model of inherited PIGO deficiency and therapeutic potential of AAV-based gene therapy.Nature communications · 2022Article
- Lipid Dyshomeostasis and Inherited Cerebellar Ataxia.Molecular neurobiology · 2022Review
- Case report: Functional characterization of aFrontiers in genetics · 2022Article
- Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models.Human molecular genetics · 2021Article
- A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The glycosylphosphatidylinositol (GPI) anchor is a post-translational modification added to approximately 150 different proteins to facilitate proper membrane anchoring and trafficking to lipid rafts. Biosynthesis and remodeling of the GPI anchor requires the activity of over 20 distinct genes. Defects in the biosynthesis of GPI anchors in humans lead to inherited glycosylphosphatidylinositol deficiency (IGD). IGD patients display a wide range of phenotypes though the central nervous system (CNS) appears to be the most commonly affected tissue. A full understanding of the etiology of these phenotypes has been hampered by the lack of animal models due to embryonic lethality of GPI biosynthesis gene null mutants. Here we model IGD by genetically ablating GPI production in the CNS with a conditional mouse allele of phosphatidylinositol glycan anchor biosynthesis, class A (Piga) and Nestin-Cre. We find that the mutants do not have structural brain defects but do not survive past weaning. The mutants show progressive decline with severe ataxia consistent with defects in cerebellar development. We show that the mutants have reduced myelination and defective Purkinje cell development. Surprisingly, we found that Piga was expressed in a fairly restricted pattern in the early postnatal brain consistent with the defects we observed in our model. Thus, we have generated a novel mouse model of the neurological defects of IGD which demonstrates a critical role for GPI biosynthesis in cerebellar and white matter development.
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