Loss of ER and nuclear envelope-associated neutral sphingomyelinase SMPD4 causes a severe neurodevelopmental disorder with microcephaly and congenital arthrogryposis
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ABSTRACT:
PROVIDER: PRJNA550547 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9600560_1.fastq.gz | Fastqsanger.gz | |||
| SRR9600560_2.fastq.gz | Fastqsanger.gz | |||
| SRR9600554_1.fastq.gz | Fastqsanger.gz | |||
| SRR9600554_2.fastq.gz | Fastqsanger.gz | |||
| SRR9600555_1.fastq.gz | Fastqsanger.gz |
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Project description:Several neurodevelopmental processes including neuronal survival, migration and differentiation are controlled by sphingolipid metabolism. Sphingomyelin is an abundant component of cell membranes. Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. While the role of acid sphingomyelinase is well established, the role of neutral sphingomyelinases in human neurodevelopment has remained elusive. Twenty-five children from ten unrelated families presented with microcephaly with simplified gyral pattern, cerebellar hypoplasia, severe developmental encephalopathy, congenital arthrogryposis, diabetes mellitus and early fetal/-postnatal demise. All probands tested have biallelic loss of function variants in SMPD4, coding for neutral sphingomyelinase-3 (nSMase-3 / SMPD4). Fibroblasts from affected individuals showed morphologic endoplasmic reticulum (ER) cisternae abnormalities and increased autophagy, consistent with a previously suggested function of SMPD4 in the ER. Overexpression of human Myc-tagged SMPD4 in HEK293T cells showed localization to both the outer nuclear envelope and the ER. Previous studies localized SMPD4 to the outer nuclear membrane. Mass spectrometry of SMPD4-associated proteins detected peptides belonging to nuclear pore complex proteins. After downregulation of SMPD4 by siRNA, delayed cell cycle progression was observed and primary fibrobalsts from affected individuals were more prone to apoptosis than controls. These data are consistent with former studies in HeLa cells showing mitotic abnormalities after siSMPD4 treatment. This study provides a link between sphingolipid membrane homeostasis, cell fate and mitotic decisions indicating novel pathway in the pathogenesis of microcephaly.
2019-12-31 | GSE133264 | GEO
Project description:Regulation of brain aging by neutral sphingomyelinase 2
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Project description:Purpose: The goals of this study are to compare next generation sequencing-derived brain cortex transcriptome profiling (RNA-seq) to study the role of neutral sphingomyelinase 2 (smpd3) in brain aging. Methods: Brain cortex mRNA profiles of 10 month old (fro/+) and smpd3 total knockout (fro/fro) mice were generated by deep sequencing, in duplicate, using Illumina NovaSeq 6000. (https://en.novogene.com) Results:A total of 1462 transcripts differed between genotypes, with 891 transcripts increased and 571 transcripts decreased. Conclusions: Transcriptome differences link decreased oxidative stress and astrocyte activation in brain cortex to nSMase2 deficiency, while synaptic signaling transcripts increased in ways consistent with increased cognitive function previously demonstrated in nSMase2-deficient mice.
2022-04-27 | GSE179045 | GEO
Project description:Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia
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Project description:Ceramides generated by the activity of the neutral sphingomyelinase 2 (NSM2) play a pivotal role in stress responses in mammalian cells. Dysregulation of sphingolipid metabolism has been implicated in numerous inflammation-related pathologies. However, its influence on inflammatory cytokine-induced signaling is yet incompletely understood. Here, we used proximity labeling to explore the plasma membrane proximal protein network of NSM2 and TNFα-induced changes thereof. We established Jurkat cells stably expressing NSM2 C-terminally fused to the engineered ascorbate peroxidase 2 (APEX2). Removal of excess biotin phenol substantially improved streptavidin-based affinity purification of biotinylated proteins. Using our optimized protocol, we determined NSM2-proximal biotinylated proteins and their changes within the first 5 min of TNFα stimulation by quantitative mass spectrometry. We observed significant dynamic changes in the NSM2 microenvironment in response to TNFαstimulation consistent with rapid remodeling of protein networks. Our data confirmed known NSM2 interactors and revealed that the recruitment of most proteins depended on NSM2 enzymatic activity. We measured significant enrichment of proteins related to vesicle-mediated transport, including proteins of recycling endosomes, trans-Golgi network, and exocytic vesicles in the proximitome of enzymatically active NSM2 within the first minutes of TNFα stimulation. Hence, the NSM2 proximal network and its TNFα-induced changes provide a valuable resource for further investigations into the involvement of NSM2 in the early signaling pathways triggered by TNFα.
2024-07-05 | PXD052930 | Pride
Project description:SMPD4 (neutral sphingomyelinase-3/nSMase3) has recently been shown to be a new cause of microcephaly in a cohort of twenty-three pediatric patients. The function of nSMases in brain development and how SMPD4 variants cause human microcephaly and cerebellar hypoplasia was previously unknown.We developed an iPSC model to complement our mouse study. We found iPSC models from human SMPD4 patient and CRISPR/Cas9-induced SMPD4 knockout lines demonstrate a proliferation defect, increased cell death, loss of neural progenitors, and shortened primary cilia. Treatment with exogenous ceramide significantly rescues the cilia defect. SMPD4 patient and knockout cells have altered WNT signaling. We provide evidence that SMPD4 controls brain development by providing ceramide for primary ciliogenesis, suggesting a novel therapeutic strategy for SMPD4 mediated disease.
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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:Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrated dysregulation of genes associated with neurogenesis, cognitive impairment and autism. This involved perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which showed normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which showed microcephaly, both demonstrated learning and memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.
2024-12-09 | GSE283523 | GEO
Project description:Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrated dysregulation of genes associated with neurogenesis, cognitive impairment and autism. This involved perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which showed normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which showed microcephaly, both demonstrated learning and memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.
2024-12-09 | GSE283525 | GEO
Project description:Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrated dysregulation of genes associated with neurogenesis, cognitive impairment and autism. This involved perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which showed normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which showed microcephaly, both demonstrated learning and memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.
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