Biallelic deleterious variants in SNAPIN, a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder [2]
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ABSTRACT:
PROVIDER: PRJNA1272074 | ENA |
REPOSITORIES: ENA
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Project description:Biallelic deleterious variants in SNAPIN, a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder [1]
| PRJNA1272071 | ENA
Project description:Fetal brain anomalies identified by prenatal ultrasound and/or magnetic resonance imaging represent a considerable healthcare burden with ~1-2/1,000 live births. To identify underlying etiology, trio prenatal exome sequencing or genome sequencing (ES/GS) has emerged as a comprehensive diagnostic paradigm with a reported diagnostic rate up to ~32%. Here, we report five unrelated families with six affected cases that presented neuroanatomical, craniofacial, and skeletal anomalies, all harboring rare, biallelic deleterious variants in SNAPIN, encoding SNARE-associated protein. SNAPIN is a ubiquitously expressed component of the autophagy-lysosomal pathway that catalyzes retrograde axonal transport and synaptic transmission. To investigate the role of SNAPIN in brain development, we generated zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes. Two independent, genetically stable snapin mutants exhibited pre-adulthood lethality, reduced overall length, disproportionately smaller head size, and altered brain morphology. Transcriptomic profiling of snapin mutant zebrafish heads revealed an early and progressive transcriptomic shift marked by autophagy activation with concomitant downregulation of structural and neurodevelopmental genes. Assessment of brain cellular ultrastructure with electron microscopy and LC3-II immunoblotting revealed retrograde vesicle transport defects, with accumulation of late endosomes and autophagosomes. Together, these findings support SNAPIN as a likely causal gene for a severe neurodevelopmental syndrome and expand the growing list of autophagy-lysosome pathway regulators essential for human brain development.
2025-08-14 | GSE298994 | GEO
Project description:Fetal brain anomalies identified by prenatal ultrasound and/or magnetic resonance imaging represent a considerable healthcare burden with ~1-2/1,000 live births. To identify underlying etiology, trio prenatal exome sequencing or genome sequencing (ES/GS) has emerged as a comprehensive diagnostic paradigm with a reported diagnostic rate up to ~32%. Here, we report five unrelated families with six affected cases that presented neuroanatomical, craniofacial, and skeletal anomalies, all harboring rare, biallelic deleterious variants in SNAPIN, encoding SNARE-associated protein. SNAPIN is a ubiquitously expressed component of the autophagy-lysosomal pathway that catalyzes retrograde axonal transport and synaptic transmission. To investigate the role of SNAPIN in brain development, we generated zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes. Two independent, genetically stable snapin mutants exhibited pre-adulthood lethality, reduced overall length, disproportionately smaller head size, and altered brain morphology. Transcriptomic profiling of snapin mutant zebrafish heads revealed an early and progressive transcriptomic shift marked by autophagy activation with concomitant downregulation of structural and neurodevelopmental genes. Assessment of brain cellular ultrastructure with electron microscopy and LC3-II immunoblotting revealed retrograde vesicle transport defects, with accumulation of late endosomes and autophagosomes. Together, these findings support SNAPIN as a likely causal gene for a severe neurodevelopmental syndrome and expand the growing list of autophagy-lysosome pathway regulators essential for human brain development.
2025-08-14 | GSE298991 | GEO
Project description:Viruses interact with the intracellular transport machinery to promote viral replication. Such host-virus interactions can drive host gene adaptation, leaving signatures of pathogen-driven evolution in host genomes. Here we leverage these genetic signatures to identify the dynein activating adaptor, ninein-like (NINL), as a critical component in the antiviral innate immune response and as a target of viral antagonism. Unique among genes en¬¬coding for dynein subunits, subunits of its co-factor dynactin, and dynein activating adaptors, NINL has evolved under recurrent positive selection, specifically in its carboxy-terminal cargo binding region. Consistent with a role for NINL in host immunity, NINL knockout cells are more permissive to viral replication as a result of a severe attenuation of interferon stimulated gene (ISG) production following interferon treatment. Moreover, we show that proteases encoded by diverse picornaviruses and coronaviruses cleave and disrupt NINL function in a host- and virus-specific manner. Our work reveals the importance of NINL in the antiviral response and the utility of using signatures of host-virus conflicts to uncover new components of antiviral immunity and targets of viral antagonism.
2022-07-08 | GSE206784 | GEO
Project description:The whole-cell scale spatial organization of lysosomes is regulated by their bidirectional motility on microtubule tracks. Small GTP-binding (G) protein, Arl8b, stimulates the anterograde transport of lysosomes by recruiting adaptor protein SKIP (also known as PLEKHM2), which in turn couples the microtubule motor kinesin-1. Here, we have identified an Arl8b effector, RUN and FYVE domaincontaining protein family member 3, RUFY3, which drives the retrograde transport of lysosomes. Artificial targeting of RUFY3 to the surface of mitochondria was sufficient to drive their perinuclear positioning. We find that RUFY3 interacts with the JIP4-Dynein-Dynactin complex and mediates Arl8b association with the retrograde motor complex. The mobile fraction of the total lysosomes per cell was significantly enhanced upon RUFY3 depletion, suggesting that RUFY3 maintains the lysosomes clustering within the perinuclear cloud. Expectedly, RUFY3 knockdown disrupted the perinuclear positioning of lysosomes upon nutrient starvation and/or serum depletion, although lysosome continued to undergo fusion with autophagosomes. Interestingly, lysosome fission events were more frequent in RUFY3-depleted cells and accordingly, there was a striking reduction in lysosome size, an effect that was also observed
2022-03-23 | PXD027010 | Pride
Project description:The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits, and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways. Here, we identified that DOK6 is required for the maintenance of peripheral axons, and loss of Dok6 can cause typical peripheral neuropathy symptoms in mice, manifested as impaired sensory, abnormal posture, paws deformities, blocked nerve conduction, and dysmyelination. Furthermore, genetic deletion of Dok6 in peripheral neurons led to axonal degeneration and hindered retrograde axonal transport. Specifically, DOK6 acts as an adaptor protein for selectivity-mediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not TrkA and TrkB. DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation, including MAP1B, Tau and Dynein for axonal transport, and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis. This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies or other degenerative diseases.
2024-02-02 | GSE249502 | GEO
Project description:The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium lead to ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal deformation. Motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport in the cilium. WDR34, a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations, some as compound mutations with other dynein-2 or IFT proteins, identified in Jeune syndrome, Short-Rib Polydactyly Syndrome or Asphyxiating thoracic dysplasia patients by stably expressing the mutant proteins in WDR34 knockout cells. WDR34 mutations led to different spectrums of phenotypes. Here, we have used quantitative proteomics demonstrated changes in dynein-2 assembly. These data re[resent pilot experiments subsequently developed fully and deposited as PXD032758.
2024-04-15 | PXD046827 | Pride
Project description:The dynein motor complex mediates polarised trafficking of a wide variety of organelles, intracellular vesicles and macromolecules. These functions are dependent on the dynactin 5 complex, which helps recruit cargoes to dynein’s tail region and activates motor movement. How dynein and dynactin orchestrate trafficking of diverse cargoes is unclear. Here, we identify HEATR5B, an interactor of the AP1 clathrin adaptor complex, as a novel player in dynein-dynactin function. HEATR5B is one of several proteins recovered in a biochemical screen for proteins whose association with the human dynein tail complex is augmented by 10 dynactin. We show that HEATR5B binds directly to the dynein tail and dynactin and stimulates motility of AP1-associated endosomal membranes in human cells. We also demonstrate that the HEATR5B homologue in Drosophila is an essential gene that promotes dynein-based transport of AP1-bound membranes to the Golgi apparatus. As HEATR5B lacks the coiledcoil architecture typical of dynein adaptors, our data point to a non-canonical process 15 orchestrating motor function on a specific cargo. We additionally show that HEATR5B promotes association of AP1 with endosomal membranes in a dynein-independent manner. Thus, HEATR5B co-ordinates multiple events in AP1-based trafficking.
2023-10-20 | PXD043387 | Pride
Project description:Distinct retrograde signaling pathways have been identified for several cellular organelles. These pathways are important to maintain the function of these organelles in response to organelle-specific stress. Using Caenorhabditis elegans, we show for the first time that such a retrograde signaling also exists for peroxisomes. Analysis of the C. elegans transcriptome revealed that peroxisomal import stress caused by the knock-down of the peroxisomal matrix protein import receptor prx-5/PEX5 induces the compensatory up-regulation of genes involved in defense response and lipid metabolic processes, especially peroxisomal beta oxidation. We, therefore, propose that the peroxisomal retrograde signaling participates in the maintenance of peroxisomal function in response to peroxisomal import stress.
2020-12-19 | GSE156318 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE35551: Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (1) GSE35552: Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (2) GSE35553: Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression (3) Refer to individual Series
2012-04-04 | E-GEOD-35554 | biostudies-arrayexpress