ArticleBrain : a journal of neurology2024
Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.
Article in Brain : a journal of neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Mapping the Cerebral Organoid Landscape: A Systematic Review of Preclinical 3D Models in Neuroscience.Advanced healthcare materials · 2026Pooled it
- Light- and chemical-induced ciliary signaling governs dorsal/ventral regionalization of human telencephalic organoids.Nature communications · 2026Article
- FABP7 controls radial glial scaffold stability during human cortical development.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Identification of stem cell marker-positive subpopulations in the vocal fold of the larynx through transcriptomic analyses.Nature communications · 2026Article
- Brain organoid models of SZT2-related disease reveal an overproduction of outer radial glial cells through mTORC1 activation.Scientific reports · 2026Article
- Patatin-Like Phospholipase Domain-Containing Protein 8 Mutation Associated with Gonadal Dysgenesis, Cerebellar Ataxia, and Peripheral Neuropathy in an Indian Family.Annals of Indian Academy of Neurology · 2025Article
- The balancing act between lipid droplets and lysosomes for membrane functionality in age-related neurodegeneration and inflammation.Progress in lipid research · 2025Review
- Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.Brain : a journal of neurology · 2025Article
- The space-time continuum in neurological disorders of the autophagosome-lysosome fusion machinery.Autophagy reports · 2025Review
- Novel PNPLA8 variants associated with primary ovarian insufficiency, tremors, cerebellar ataxia and limb weakness: a case report and literature review.Journal of neurology · 2024Review
- Using cortical organoids to understand the pathogenesis of malformations of cortical development.Frontiers in neuroscience · 2024Review
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Authors and funding
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Abstract
Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
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