Biallelic null variants in PNPLA8 cause microcephaly through the reduced abundance of basal radial gliaナカセンセイキニュウ
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA956892 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24203794_1.fastq.gz | Fastqsanger.gz | |||
| SRR24203794_2.fastq.gz | Fastqsanger.gz | |||
| SRR24203795_1.fastq.gz | Fastqsanger.gz | |||
| SRR24203795_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:PNPLA8, one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological conditions through the maintenance of membrane phospholipids. However, little is known about its role in brain development. Here, we report 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide spectrum of clinical features ranging from developmental and epileptic-dyskinetic encephalopathy (DEDE) to progressive movement disorders and no phenotype depending on the variants and their positions. Complete loss of PNPLA8 was associated with the severe end of the spectrum showing DEDE manifestations and congenital or progressive microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells (iPSCs), we found that loss of PNPLA8 reduces the abundance of basal radial glial cells (bRGCs) and upper-layer neurons. By spatial transcriptomic analysis targeting apical radial glial cells (aRGCs), we found the downregulation of bRGC-related gene sets in patient-derived cerebral organoids. Lipidomic analysis revealed a decrease in the amount of lysophosphatidic acid, lysophosphatidylethanolamine, and phosphatidic acid, indicative of the disturbed phospholipid metabolism in PNPLA8 knockout neural progenitor cells. Our data suggest that PNPLA8 has a critical role in the bRGC-mediated expansion of the developing human cortex by regulating the fate commitment of aRGCs.
2024-03-05 | GSE248252 | GEO
Project description:PNPLA8, one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological conditions through the maintenance of membrane phospholipids. However, little is known about its role in brain development. Here, we report 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide spectrum of clinical features ranging from developmental and epileptic-dyskinetic encephalopathy (DEDE) to progressive movement disorders and no phenotype depending on the variants and their positions. Complete loss of PNPLA8 was associated with the severe end of the spectrum showing DEDE manifestations and congenital or progressive microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells (iPSCs), we found that loss of PNPLA8 reduces the abundance of basal radial glial cells (bRGCs) and upper-layer neurons. By spatial transcriptomic analysis targeting apical radial glial cells (aRGCs), we found the downregulation of bRGC-related gene sets in patient-derived cerebral organoids. Lipidomic analysis revealed a decrease in the amount of lysophosphatidic acid, lysophosphatidylethanolamine, and phosphatidic acid, indicative of the disturbed phospholipid metabolism in PNPLA8 knockout neural progenitor cells. Our data suggest that PNPLA8 has a critical role in the bRGC-mediated expansion of the developing human cortex by regulating the fate commitment of aRGCs.ナカセンセイキニュウ
2023-05-03 | GSE229956 | GEO
Project description:Biallelic null variants in PNPLA8 cause microcephaly through the reduced abundance of basal radial glia
| PRJNA1043109 | ENA
Project description: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.
| S-EPMC11531855 | biostudies-literature
Project description:Inactivation of the minor spliceosome has been linked to microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). To interrogate how minor intron splicing regulates cortical development, we employed Emx1-Cre to ablate Rnu11, which encodes the minor spliceosome-specific U11 small nuclear RNA (snRNA), in the developing cortex (pallium). Rnu11 cKO mice were born with microcephaly, caused by death of self-amplifying radial glial cells (RGCs). However, both intermediate progenitor cells (IPCs) and neurons were produced in the U11-null pallium. RNAseq of the pallium revealed elevated minor intron retention in the mutant, particularly in genes regulating cell cycle. Moreover, the only downregulated minor intron-containing gene (MIG) was Spc24, which regulates kinetochore assembly. These findings were consistent with the observation of fewer RGCs entering cytokinesis prior to RGC loss, underscoring the requirement of minor splicing for cell cycle progression in RGCs. Overall, we provide a potential explanation of how disruption of minor splicing might cause microcephaly in MOPD1.
2018-06-05 | GSE96616 | GEO
Project description:Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia
| PRJNA951710 | ENA
Project description:The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, mainly results from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lisencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion; that oRGs are necessary for neocortical folding; and that defects in oRG expansion may cause primary microcephaly.
2022-08-31 | GSE211990 | GEO
Project description:Neurodevelopmental disorders have great clinical and genetic heterogeneity and are known to arise from dysfunction in components of diverse cellular pathways, the precise pathomechanism for the majority however remains elusive. We studied five patients from three unrelated families originating from Yemen, Germany and Spain. The affected individuals manifested global developmental delay, variable degrees of microcephaly and hypotonia. Whole exome sequencing identified biallelic variants in the ZFTRAF1, encoding a protein of unknown function. The four patients from two unrelated families segregated two homozygous frameshift variants, NM_001330618.2:c.1085_1086delTT;p.(Phe362Cysfs*18), NM_001330618.2:c.1162_1163delCT;p.(Leu388Glyfs*49) whereas the third family carried an intronic variant NM_001330618.2:c.612-2A>C;p.(?). We studied this protein at the cellular level and show that endogenous ZFTRAF1 is a nucleocytoplasmic protein with predominant nuclear expression in different human cell lines. We also investigated ZFTRAF1 interactome by pulldown assay and identified 110 interacting proteins that are the crucial components of mRNA processing and autophagy-related pathways. ZFTRAF1 was completely absent in primary fibroblasts derived from two independent patients. Posthoc, profiling of autophagy markers, whole-transcriptome, and whole-proteome analyses discovered dysfunctional autophagy in patient-derived fibroblasts. The same, when attempted to be reprogrammed, could only achieve the pre-iPSCs phase, another indication of impaired autophagy. Briefly, discovered ZFTRAF1 as an indispensable novel component of neurodevelopment, and through multiple lines of evidence implicate its role in autophagy. Our findings suggest that biallelic variants of ZFTRAF1 cause severe neurodevelopmental disability syndrome and the loss-of-function leads to deficient autophagy and mRNA processing, both of which have crucial roles in normal human brain development.
2024-10-17 | PXD044735 | Pride
Project description:Neural cell type diversity arises from both spatial and temporal patterning of neural stem cells. Although spatial patterning mechanisms have been extensively studied, temporal patterning mechanisms remain relatively unexplored. In this study, we addressed generation of diverse neural cell types through lineage progression of mouse cortical radial glia. The time series scRNA-seq and snATAC-seq of mouse cortical development revealed that radial glia temporally transitioned from neurogenesis to gliogenesis. During gliogenic stages, various cell types were generated simultaneously along multidirectional lineage trajectories. We established comprehensive molecular maps for cortical lineage commitment and cellular diversification. The transcriptome and epigenome of cortical radial glia exhibit temporal dynamics, as revealed by scRNA-seq and snATAC-seq. Lhx2, a transcription factor with temporal dynamic chromatin binding activities, was identified as a key regulator of the neurogenesis-to-gliogenesis transition. It maintains neurogenic competence by establishing the active epigenetic state of its target genes.
2025-06-05 | GSE298892 | GEO
Project description:Neural cell type diversity arises from both spatial and temporal patterning of neural stem cells. Although spatial patterning mechanisms have been extensively studied, temporal patterning mechanisms remain relatively unexplored. In this study, we addressed generation of diverse neural cell types through lineage progression of mouse cortical radial glia. The time series scRNA-seq and snATAC-seq of mouse cortical development revealed that radial glia temporally transitioned from neurogenesis to gliogenesis. During gliogenic stages, various cell types were generated simultaneously along multidirectional lineage trajectories. We established comprehensive molecular maps for cortical lineage commitment and cellular diversification. The transcriptome and epigenome of cortical radial glia exhibit temporal dynamics, as revealed by scRNA-seq and snATAC-seq. Lhx2, a transcription factor with temporal dynamic chromatin binding activities, was identified as a key regulator of the neurogenesis-to-gliogenesis transition. It maintains neurogenic competence by establishing the active epigenetic state of its target genes.
2024-09-03 | GSE276209 | GEO