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Loss of ER and nuclear envelope-associated neutral sphingomyelinase SMPD4 causes a severe neurodevelopmental disorder with microcephaly and congenital arthrogryposis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133264 | GEO | 2019/12/31

REPOSITORIES: GEO

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Project description:We have used human umbilical vein endothelial cell line (HUVEC) as a model to investigate the effect of ultrasound (US) activated micro-bubbles on sensitizing the tumour response to radiation and to check the implication of this approach on gene expression. The use of micro-bubbles in cancer therapy is a novel approach that is being recently investigated, and patterns of gene expressions were not yet characterized. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach.

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Loss of ER and nuclear envelope-associated neutral sphingomyelinase SMPD4 causes a severe neurodevelopmental disorder with microcephaly and congenital arthrogryposis

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