{"gene":"SNX14","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2015,"finding":"SNX14 localizes to lysosomes and associates with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes; loss of SNX14 causes engorged lysosomes and slower autophagosome clearance upon starvation-induced autophagy","method":"Subcellular fractionation/localization, patient-derived cell autophagy flux assays, zebrafish morphant accumulation of autophagosomes","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, lipid binding, patient cells, zebrafish model), replicated across labs","pmids":["25848753"],"is_preprint":false},{"year":2014,"finding":"SNX14 knockdown in neurons reduces intrinsic excitability and severely impairs both excitatory and inhibitory synaptic transmission; SNX14 protein levels increase progressively during neuronal development and maturation","method":"Knockdown (shRNA/siRNA) with electrophysiological readouts in mouse neurons; laser capture microdissection for imprinting analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined electrophysiological phenotype, single lab","pmids":["24859318"],"is_preprint":false},{"year":2015,"finding":"SNX14 directly interacts with the serotonin 5-HT6 receptor and promotes its internalization and lysosomal degradation; the RGS domain of SNX14 binds and sequesters Gαs to inhibit cAMP production; PKA-mediated phosphorylation of SNX14 inhibits Gαs binding and redirects SNX14 to promote 5-HT6R endocytic degradation","method":"Co-immunoprecipitation, receptor internalization assays, cAMP measurement, PKA phosphorylation assay, knockdown rescue experiments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional assays, single lab with multiple orthogonal methods","pmids":["25795301"],"is_preprint":false},{"year":2018,"finding":"SNX14 is an ER-resident protein requiring its N-terminal transmembrane helices for ER localization (PX domain is dispensable for localization); SNX14 loss causes cholesterol accumulation in LAMP1-positive lysosomal structures and perturbed neutral lipid metabolism; SNX14 associates with ER-derived lipid droplets following oleate treatment; ER-late endosome/lysosome contact sites are maintained in SNX14KO cells, indicating SNX14 is not required for ER-endolysosomal tethering","method":"Domain deletion/mutagenesis for localization, filipin staining, cholesterol ester measurement, oleate treatment LD association, SNX14KO HEK293 cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — domain mutagenesis combined with multiple functional assays (lipid staining, lipidomics, KO cells), single lab with orthogonal methods","pmids":["29635513"],"is_preprint":false},{"year":2019,"finding":"Snx14 is an ER-resident protein that localizes to ER-lipid droplet (ER-LD) contact sites following fatty acid treatment, where it promotes LD maturation/growth while remaining ER-anchored and binding LDs in trans; Snx14 accumulates at ER microdomains containing the fatty acyl-CoA ligase ACSL3 where nascent LDs bud; Snx14 localization to ER-LD contacts is independent of Seipin","method":"APEX2 proximity labeling, live imaging, topological dissection, Snx14 KO morphology analysis, multi-time point imaging, co-localization with ACSL3","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — APEX2 proximity labeling plus live imaging plus KO phenotype, single lab with strong orthogonal methods","pmids":["30765438"],"is_preprint":false},{"year":2020,"finding":"Snx14 functions as an ER-LD tethering protein required to maintain lipid saturation balance; SNX14KO cells show ER integrity compromise and hypersensitivity to saturated fatty acid-mediated lipotoxic cell death; APEX2 proximity labeling reveals functional interaction between Snx14 and Δ-9 FA desaturase SCD1; SNX14KO cells increase membrane lipid saturation following palmitate exposure, phenocopying SCD1-impaired cells; lipotoxicity in SNX14KO cells can be rescued by SCD1 overexpression","method":"APEX2 proximity labeling, lipidomic profiling, SCD1 overexpression rescue, lipotoxicity assays in SNX14KO and SCAR20 patient-derived cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — APEX2 proteomics plus lipidomics plus genetic rescue, multiple orthogonal methods in single study with patient cell validation","pmids":["33310904"],"is_preprint":false},{"year":2021,"finding":"SNX14 deficiency destabilizes the microtubule-severing enzyme spastin, disrupts microtubule organization and axonal mitochondrial transport in Purkinje cells, leading to compromised axonal integrity and mitochondrial dysfunction; the antiepileptic drug valproate restores mitochondrial transport and function and ameliorates motor deficits in Snx14-deficient mice","method":"Snx14-deficient mouse model, motor behavior tests, spastin protein level analysis, live axonal mitochondrial transport imaging, valproate treatment rescue","journal":"National science review","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype and mechanistic link to spastin, single lab","pmids":["34691693"],"is_preprint":false},{"year":2021,"finding":"Yeast Mdm1 (SNX14 ortholog) at the nucleus-vacuole junction (NVJ) mediates TORC1 inactivation-induced nucleolar protein migration and proper nucleophagic degradation of nucleolar proteins, while being dispensable for the induction of nucleophagic flux itself","method":"Genetic deletion of Mdm1 in yeast, fluorescence microscopy of nucleolar dynamics, nucleophagic flux assays under nutrient starvation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype in yeast ortholog, single lab","pmids":["33740659"],"is_preprint":false},{"year":2024,"finding":"SNX14-deficient Purkinje cells show lipid storage and metabolism defects including accumulation of acylcarnitines and depletion of triglycerides in predegenerating cerebella; lipid droplet content defects and telolysosome enlargement suggest lipotoxicity as the pathogenic mechanism of SNX14 deficiency-driven Purkinje cell neurodegeneration","method":"SNX14-deficient mouse model, ultrastructural analysis (electron microscopy), lipidomic profiling, immunohistochemistry for Purkinje cell markers","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with ultrastructure and lipidomics, single lab","pmids":["38625743"],"is_preprint":false},{"year":2025,"finding":"SNX14 regulates GluA2 (AMPA receptor subunit) protein levels by promoting GluA2 degradation via the lysosomal pathway, thereby influencing glutamatergic synaptic transmission; SNX14 knockdown in hippocampus decreases seizure susceptibility while overexpression increases it","method":"SNX14 knockdown and overexpression in mouse hippocampus, western blotting for GluA2, lysosomal inhibition assays, seizure susceptibility behavioral assays","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with defined molecular target and pathway, single lab","pmids":["40237949"],"is_preprint":false}],"current_model":"SNX14 is an ER-resident transmembrane protein (anchored via N-terminal helices) that localizes to ER-lipid droplet contact sites to promote lipid droplet growth and regulate fatty acid saturation balance through functional interaction with the desaturase SCD1; it also associates with PI(3,5)P2-positive late endosomes/lysosomes to support autophagosome clearance, acts as a dual negative regulator of 5-HT6R signaling by sequestering Gαs and promoting receptor lysosomal degradation, and in neurons supports axonal mitochondrial transport by stabilizing the microtubule-severing enzyme spastin — loss of SNX14 causes lipotoxicity, lysosomal dysfunction, and Purkinje cell neurodegeneration underlying SCAR20 cerebellar ataxia."},"narrative":{"teleology":[{"year":2014,"claim":"Establishing a neuronal role: SNX14 was shown to be required for normal synaptic transmission and intrinsic excitability in neurons, with expression increasing during neuronal maturation, revealing that this sorting nexin has a critical neuronal function beyond vesicle trafficking.","evidence":"shRNA knockdown in mouse neurons with electrophysiological recordings","pmids":["24859318"],"confidence":"Medium","gaps":["Molecular target(s) mediating synaptic transmission effects not identified","Single lab without independent replication","Mechanism linking SNX14 loss to reduced excitability undefined"]},{"year":2015,"claim":"Linking SNX14 to endolysosomal function and disease: SNX14 was found to associate with PI(3,5)P2-positive late endosomes/lysosomes, and its loss caused lysosomal engorgement and impaired autophagosome clearance, directly connecting biallelic SNX14 mutations to SCAR20 cerebellar ataxia.","evidence":"Subcellular fractionation, lipid binding assays, patient-derived fibroblast autophagy flux, zebrafish morphant phenotyping","pmids":["25848753"],"confidence":"High","gaps":["Mechanism by which SNX14 facilitates autophagosome–lysosome fusion was not defined","Whether the lysosomal phenotype is primary or secondary to ER lipid defects was unclear"]},{"year":2015,"claim":"Defining a GPCR signaling regulatory mechanism: SNX14 was shown to act as a dual negative regulator of 5-HT6R signaling—its RGS domain sequesters Gαs to suppress cAMP, while PKA-dependent phosphorylation of SNX14 switches it to promote 5-HT6R internalization and lysosomal degradation, establishing a feedback circuit.","evidence":"Reciprocal co-immunoprecipitation, cAMP measurement, receptor internalization assays, PKA phosphorylation assays, knockdown rescue in HEK293 cells","pmids":["25795301"],"confidence":"Medium","gaps":["In vivo relevance of 5-HT6R regulation by SNX14 not tested","Whether RGS domain activity extends to other Gα subunits unknown","Single lab study"]},{"year":2018,"claim":"Redefining SNX14 as an ER-resident protein: domain mutagenesis established that N-terminal transmembrane helices (not the PX domain) anchor SNX14 to the ER, and SNX14 knockout caused cholesterol and neutral lipid accumulation in lysosomes without disrupting ER–endolysosome contact sites, shifting the primary functional assignment from endosome to ER.","evidence":"Domain deletion constructs, filipin staining, cholesterol ester quantification, oleate-induced LD association in SNX14-KO HEK293 cells","pmids":["29635513"],"confidence":"High","gaps":["Structural basis of ER anchoring not resolved","Whether cholesterol accumulation is a direct lipid transport defect or secondary unclear"]},{"year":2019,"claim":"Establishing ER–lipid droplet contact site function: SNX14 was shown to localize to ER–LD contacts in trans following fatty acid treatment, accumulating at ACSL3-positive ER microdomains where nascent LDs bud, and promoting LD maturation/growth independently of Seipin.","evidence":"APEX2 proximity labeling, live imaging, topological dissection, KO morphology analysis in U2OS cells","pmids":["30765438"],"confidence":"High","gaps":["Direct lipid transfer activity not demonstrated","Structural basis of LD binding in trans unknown","Whether SNX14 directly senses nascent LD budding or is passively recruited unclear"]},{"year":2020,"claim":"Connecting SNX14 to fatty acid desaturation and lipotoxicity: APEX2 proteomics identified SCD1 as a functional partner, and SNX14 loss phenocopied SCD1 impairment by increasing membrane lipid saturation and sensitizing cells to palmitate-induced lipotoxic death—a phenotype rescued by SCD1 overexpression—establishing lipotoxicity as the cellular pathomechanism in SCAR20.","evidence":"APEX2 proximity labeling, lipidomic profiling, SCD1 overexpression rescue, lipotoxicity assays in SNX14-KO and SCAR20 patient fibroblasts","pmids":["33310904"],"confidence":"High","gaps":["Whether SNX14 directly modulates SCD1 enzymatic activity or substrate access unknown","Tissue-specific lipotoxic thresholds in Purkinje cells not quantified"]},{"year":2021,"claim":"Revealing a microtubule/mitochondrial transport role in neurodegeneration: SNX14 deficiency was found to destabilize spastin, disrupt microtubule organization and axonal mitochondrial transport in Purkinje cells, with valproate rescuing both mitochondrial transport and motor deficits in vivo, adding a cytoskeletal dimension to the SCAR20 mechanism.","evidence":"Snx14-deficient mouse model, spastin protein quantification, live axonal mitochondrial transport imaging, valproate treatment rescue","pmids":["34691693"],"confidence":"Medium","gaps":["Mechanism by which SNX14 stabilizes spastin not defined","Whether spastin destabilization is a direct interaction or mediated by lipid changes unknown","Single lab"]},{"year":2024,"claim":"Validating lipotoxicity as the in vivo Purkinje cell death mechanism: lipidomic and ultrastructural analysis of predegenerating SNX14-deficient cerebella revealed acylcarnitine accumulation, triglyceride depletion, LD content defects, and telolysosome enlargement, confirming that lipid storage failure precedes neurodegeneration.","evidence":"SNX14-deficient mouse cerebella, electron microscopy, lipidomic profiling, immunohistochemistry","pmids":["38625743"],"confidence":"Medium","gaps":["Causal chain from lipid storage defect to Purkinje cell death not fully delineated","Contribution of lysosomal versus ER dysfunction not resolved in vivo","Single lab"]},{"year":2025,"claim":"Identifying GluA2 as a neuronal substrate: SNX14 was shown to promote lysosomal degradation of the AMPA receptor subunit GluA2, thereby regulating glutamatergic transmission and seizure susceptibility, expanding its membrane protein trafficking repertoire beyond 5-HT6R.","evidence":"SNX14 knockdown and overexpression in mouse hippocampus, GluA2 western blotting, lysosomal inhibition, seizure behavioral assays","pmids":["40237949"],"confidence":"Medium","gaps":["Whether SNX14 directly binds GluA2 not shown","Mechanism of cargo selectivity for GluA2 versus other receptors unknown","Single lab"]},{"year":null,"claim":"Key unresolved questions include whether SNX14 directly transfers lipids at ER–LD contacts, how it mechanistically couples to SCD1 activity, the structural basis of its multi-site membrane engagement, and whether lipotoxicity and cytoskeletal defects represent parallel or convergent pathogenic pathways in SCAR20.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct lipid transfer activity demonstrated","No high-resolution structure of SNX14","Relative contributions of lipotoxicity versus spastin/microtubule defects to Purkinje cell death unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,3,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[4,5,8]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4,5,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,9]}],"complexes":[],"partners":["SCD1","ACSL3","HTR6","GNAS","GRIA2","SPAST"],"other_free_text":[]},"mechanistic_narrative":"SNX14 is an ER-anchored sorting nexin that functions at membrane contact sites to coordinate lipid metabolism, organelle homeostasis, and membrane protein trafficking. Its N-terminal transmembrane helices anchor it in the ER, where it localizes to ER–lipid droplet contact sites to promote lipid droplet growth and maintain fatty acid saturation balance through functional interaction with the Δ-9 desaturase SCD1; loss of SNX14 causes saturated fatty acid–driven lipotoxicity, lysosomal cholesterol accumulation, and impaired autophagosome clearance [PMID:29635513, PMID:30765438, PMID:33310904, PMID:25848753]. Through its RGS domain, SNX14 sequesters Gαs to inhibit cAMP signaling downstream of the 5-HT6 receptor and promotes receptor lysosomal degradation, while in neurons it stabilizes the microtubule-severing enzyme spastin to support axonal mitochondrial transport and also regulates GluA2 AMPA receptor levels via lysosomal degradation [PMID:25795301, PMID:34691693, PMID:40237949]. Biallelic loss-of-function mutations in SNX14 cause spinocerebellar ataxia autosomal recessive 20 (SCAR20), driven by lipotoxic Purkinje cell degeneration characterized by acylcarnitine accumulation, triglyceride depletion, and telolysosome enlargement [PMID:25848753, PMID:38625743]."},"prefetch_data":{"uniprot":{"accession":"Q9Y5W7","full_name":"Sorting nexin-14","aliases":[],"length_aa":946,"mass_kda":110.2,"function":"Plays a role in maintaining normal neuronal excitability and synaptic transmission. May be involved in several stages of intracellular trafficking (By similarity). Required for autophagosome clearance, possibly by mediating the fusion of lysosomes with autophagosomes (Probable). Binds phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), a key component of late endosomes/lysosomes (PubMed:25848753). Does not bind phosphatidylinositol 3-phosphate (PtdIns(3P)) (PubMed:25148684, PubMed:25848753)","subcellular_location":"Lysosome membrane; Late endosome membrane; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q9Y5W7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX14","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CYP51A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SNX14","total_profiled":1310},"omim":[{"mim_id":"620961","title":"SORTING NEXIN 25; SNX25","url":"https://www.omim.org/entry/620961"},{"mim_id":"616354","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 20; SCAR20","url":"https://www.omim.org/entry/616354"},{"mim_id":"616105","title":"SORTING NEXIN 14; SNX14","url":"https://www.omim.org/entry/616105"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX14"},"hgnc":{"alias_symbol":["RGS-PX2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5W7","domains":[{"cath_id":"-","chopping":"19-67","consensus_level":"high","plddt":75.4447,"start":19,"end":67},{"cath_id":"-","chopping":"119-302_313-321_787-939","consensus_level":"high","plddt":85.5337,"start":119,"end":939},{"cath_id":"1.10.167.10","chopping":"336-468","consensus_level":"high","plddt":84.4071,"start":336,"end":468},{"cath_id":"3.30.1520.10","chopping":"566-576_586-682","consensus_level":"high","plddt":86.9144,"start":566,"end":682}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5W7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5W7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5W7-F1-predicted_aligned_error_v6.png","plddt_mean":73.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX14","jax_strain_url":"https://www.jax.org/strain/search?query=SNX14"},"sequence":{"accession":"Q9Y5W7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5W7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5W7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5W7"}},"corpus_meta":[{"pmid":"25848753","id":"PMC_25848753","title":"Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25848753","citation_count":103,"is_preprint":false},{"pmid":"30765438","id":"PMC_30765438","title":"Cerebellar ataxia disease-associated Snx14 promotes lipid droplet growth at ER-droplet contacts.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30765438","citation_count":95,"is_preprint":false},{"pmid":"25439728","id":"PMC_25439728","title":"Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25439728","citation_count":85,"is_preprint":false},{"pmid":"29635513","id":"PMC_29635513","title":"SNX14 mutations affect endoplasmic reticulum-associated neutral lipid metabolism in autosomal recessive spinocerebellar ataxia 20.","date":"2018","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29635513","citation_count":56,"is_preprint":false},{"pmid":"24859318","id":"PMC_24859318","title":"Snx14 regulates neuronal excitability, promotes synaptic transmission, and is imprinted in the brain of mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24859318","citation_count":33,"is_preprint":false},{"pmid":"25795301","id":"PMC_25795301","title":"SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25795301","citation_count":28,"is_preprint":false},{"pmid":"36670083","id":"PMC_36670083","title":"Apoptotic Vesicles Regulate Bone Metabolism via the miR1324/SNX14/SMAD1/5 Signaling Axis.","date":"2023","source":"Small (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36670083","citation_count":25,"is_preprint":false},{"pmid":"27566131","id":"PMC_27566131","title":"Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed.","date":"2016","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27566131","citation_count":20,"is_preprint":false},{"pmid":"34691693","id":"PMC_34691693","title":"SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate.","date":"2021","source":"National science review","url":"https://pubmed.ncbi.nlm.nih.gov/34691693","citation_count":20,"is_preprint":false},{"pmid":"33310904","id":"PMC_33310904","title":"Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33310904","citation_count":18,"is_preprint":false},{"pmid":"38625743","id":"PMC_38625743","title":"Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/38625743","citation_count":8,"is_preprint":false},{"pmid":"33740659","id":"PMC_33740659","title":"Sorting nexin Mdm1/SNX14 regulates nucleolar dynamics at the NVJ after TORC1 inactivation.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33740659","citation_count":6,"is_preprint":false},{"pmid":"33193593","id":"PMC_33193593","title":"Two Compound Heterozygous Variants in SNX14 Cause Stereotypies and Dystonia in Autosomal Recessive Spinocerebellar Ataxia 20.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33193593","citation_count":5,"is_preprint":false},{"pmid":"37485342","id":"PMC_37485342","title":"Homozygous deep intronic variant in SNX14 cause autosomal recessive Spinocerebellar ataxia 20: a case report.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37485342","citation_count":4,"is_preprint":false},{"pmid":"38869753","id":"PMC_38869753","title":"SNX14 inhibits autophagy via the PI3K/AKT/mTOR signaling cascade in breast cancer cells.","date":"2024","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/38869753","citation_count":4,"is_preprint":false},{"pmid":"35195341","id":"PMC_35195341","title":"Autosomal recessive spinocerebellar ataxia-20 due to a novel SNX14 variant in an Indian girl.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/35195341","citation_count":3,"is_preprint":false},{"pmid":"40237949","id":"PMC_40237949","title":"Inhibiting SNX14 Alleviates Epileptic Seizures by Regulating GluA2 Degradation via the Lysosomal Pathway.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40237949","citation_count":1,"is_preprint":false},{"pmid":"38655056","id":"PMC_38655056","title":"Compound heterozygous mutation of the SNX14 gene causes autosomal recessive spinocerebellar ataxia 20.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38655056","citation_count":1,"is_preprint":false},{"pmid":"41294032","id":"PMC_41294032","title":"Exploring the Genetic Variations Underlying SNX14-Linked Autosomal Recessive Spinocerebellar Ataxia Type 20: A Case Series of 17 Patients From a Single Center in the Omani Population and Review of Literature.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41294032","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10356,"output_tokens":2608,"usd":0.035094},"stage2":{"model":"claude-opus-4-6","input_tokens":5928,"output_tokens":2888,"usd":0.15276},"total_usd":0.187854,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"SNX14 localizes to lysosomes and associates with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes; loss of SNX14 causes engorged lysosomes and slower autophagosome clearance upon starvation-induced autophagy\",\n      \"method\": \"Subcellular fractionation/localization, patient-derived cell autophagy flux assays, zebrafish morphant accumulation of autophagosomes\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, lipid binding, patient cells, zebrafish model), replicated across labs\",\n      \"pmids\": [\"25848753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNX14 knockdown in neurons reduces intrinsic excitability and severely impairs both excitatory and inhibitory synaptic transmission; SNX14 protein levels increase progressively during neuronal development and maturation\",\n      \"method\": \"Knockdown (shRNA/siRNA) with electrophysiological readouts in mouse neurons; laser capture microdissection for imprinting analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined electrophysiological phenotype, single lab\",\n      \"pmids\": [\"24859318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SNX14 directly interacts with the serotonin 5-HT6 receptor and promotes its internalization and lysosomal degradation; the RGS domain of SNX14 binds and sequesters Gαs to inhibit cAMP production; PKA-mediated phosphorylation of SNX14 inhibits Gαs binding and redirects SNX14 to promote 5-HT6R endocytic degradation\",\n      \"method\": \"Co-immunoprecipitation, receptor internalization assays, cAMP measurement, PKA phosphorylation assay, knockdown rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25795301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX14 is an ER-resident protein requiring its N-terminal transmembrane helices for ER localization (PX domain is dispensable for localization); SNX14 loss causes cholesterol accumulation in LAMP1-positive lysosomal structures and perturbed neutral lipid metabolism; SNX14 associates with ER-derived lipid droplets following oleate treatment; ER-late endosome/lysosome contact sites are maintained in SNX14KO cells, indicating SNX14 is not required for ER-endolysosomal tethering\",\n      \"method\": \"Domain deletion/mutagenesis for localization, filipin staining, cholesterol ester measurement, oleate treatment LD association, SNX14KO HEK293 cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mutagenesis combined with multiple functional assays (lipid staining, lipidomics, KO cells), single lab with orthogonal methods\",\n      \"pmids\": [\"29635513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Snx14 is an ER-resident protein that localizes to ER-lipid droplet (ER-LD) contact sites following fatty acid treatment, where it promotes LD maturation/growth while remaining ER-anchored and binding LDs in trans; Snx14 accumulates at ER microdomains containing the fatty acyl-CoA ligase ACSL3 where nascent LDs bud; Snx14 localization to ER-LD contacts is independent of Seipin\",\n      \"method\": \"APEX2 proximity labeling, live imaging, topological dissection, Snx14 KO morphology analysis, multi-time point imaging, co-localization with ACSL3\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — APEX2 proximity labeling plus live imaging plus KO phenotype, single lab with strong orthogonal methods\",\n      \"pmids\": [\"30765438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Snx14 functions as an ER-LD tethering protein required to maintain lipid saturation balance; SNX14KO cells show ER integrity compromise and hypersensitivity to saturated fatty acid-mediated lipotoxic cell death; APEX2 proximity labeling reveals functional interaction between Snx14 and Δ-9 FA desaturase SCD1; SNX14KO cells increase membrane lipid saturation following palmitate exposure, phenocopying SCD1-impaired cells; lipotoxicity in SNX14KO cells can be rescued by SCD1 overexpression\",\n      \"method\": \"APEX2 proximity labeling, lipidomic profiling, SCD1 overexpression rescue, lipotoxicity assays in SNX14KO and SCAR20 patient-derived cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — APEX2 proteomics plus lipidomics plus genetic rescue, multiple orthogonal methods in single study with patient cell validation\",\n      \"pmids\": [\"33310904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX14 deficiency destabilizes the microtubule-severing enzyme spastin, disrupts microtubule organization and axonal mitochondrial transport in Purkinje cells, leading to compromised axonal integrity and mitochondrial dysfunction; the antiepileptic drug valproate restores mitochondrial transport and function and ameliorates motor deficits in Snx14-deficient mice\",\n      \"method\": \"Snx14-deficient mouse model, motor behavior tests, spastin protein level analysis, live axonal mitochondrial transport imaging, valproate treatment rescue\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype and mechanistic link to spastin, single lab\",\n      \"pmids\": [\"34691693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Mdm1 (SNX14 ortholog) at the nucleus-vacuole junction (NVJ) mediates TORC1 inactivation-induced nucleolar protein migration and proper nucleophagic degradation of nucleolar proteins, while being dispensable for the induction of nucleophagic flux itself\",\n      \"method\": \"Genetic deletion of Mdm1 in yeast, fluorescence microscopy of nucleolar dynamics, nucleophagic flux assays under nutrient starvation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype in yeast ortholog, single lab\",\n      \"pmids\": [\"33740659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX14-deficient Purkinje cells show lipid storage and metabolism defects including accumulation of acylcarnitines and depletion of triglycerides in predegenerating cerebella; lipid droplet content defects and telolysosome enlargement suggest lipotoxicity as the pathogenic mechanism of SNX14 deficiency-driven Purkinje cell neurodegeneration\",\n      \"method\": \"SNX14-deficient mouse model, ultrastructural analysis (electron microscopy), lipidomic profiling, immunohistochemistry for Purkinje cell markers\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with ultrastructure and lipidomics, single lab\",\n      \"pmids\": [\"38625743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX14 regulates GluA2 (AMPA receptor subunit) protein levels by promoting GluA2 degradation via the lysosomal pathway, thereby influencing glutamatergic synaptic transmission; SNX14 knockdown in hippocampus decreases seizure susceptibility while overexpression increases it\",\n      \"method\": \"SNX14 knockdown and overexpression in mouse hippocampus, western blotting for GluA2, lysosomal inhibition assays, seizure susceptibility behavioral assays\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with defined molecular target and pathway, single lab\",\n      \"pmids\": [\"40237949\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX14 is an ER-resident transmembrane protein (anchored via N-terminal helices) that localizes to ER-lipid droplet contact sites to promote lipid droplet growth and regulate fatty acid saturation balance through functional interaction with the desaturase SCD1; it also associates with PI(3,5)P2-positive late endosomes/lysosomes to support autophagosome clearance, acts as a dual negative regulator of 5-HT6R signaling by sequestering Gαs and promoting receptor lysosomal degradation, and in neurons supports axonal mitochondrial transport by stabilizing the microtubule-severing enzyme spastin — loss of SNX14 causes lipotoxicity, lysosomal dysfunction, and Purkinje cell neurodegeneration underlying SCAR20 cerebellar ataxia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SNX14 is an ER-anchored sorting nexin that functions at membrane contact sites to coordinate lipid metabolism, organelle homeostasis, and membrane protein trafficking. Its N-terminal transmembrane helices anchor it in the ER, where it localizes to ER–lipid droplet contact sites to promote lipid droplet growth and maintain fatty acid saturation balance through functional interaction with the Δ-9 desaturase SCD1; loss of SNX14 causes saturated fatty acid–driven lipotoxicity, lysosomal cholesterol accumulation, and impaired autophagosome clearance [PMID:29635513, PMID:30765438, PMID:33310904, PMID:25848753]. Through its RGS domain, SNX14 sequesters Gαs to inhibit cAMP signaling downstream of the 5-HT6 receptor and promotes receptor lysosomal degradation, while in neurons it stabilizes the microtubule-severing enzyme spastin to support axonal mitochondrial transport and also regulates GluA2 AMPA receptor levels via lysosomal degradation [PMID:25795301, PMID:34691693, PMID:40237949]. Biallelic loss-of-function mutations in SNX14 cause spinocerebellar ataxia autosomal recessive 20 (SCAR20), driven by lipotoxic Purkinje cell degeneration characterized by acylcarnitine accumulation, triglyceride depletion, and telolysosome enlargement [PMID:25848753, PMID:38625743].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing a neuronal role: SNX14 was shown to be required for normal synaptic transmission and intrinsic excitability in neurons, with expression increasing during neuronal maturation, revealing that this sorting nexin has a critical neuronal function beyond vesicle trafficking.\",\n      \"evidence\": \"shRNA knockdown in mouse neurons with electrophysiological recordings\",\n      \"pmids\": [\"24859318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target(s) mediating synaptic transmission effects not identified\", \"Single lab without independent replication\", \"Mechanism linking SNX14 loss to reduced excitability undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking SNX14 to endolysosomal function and disease: SNX14 was found to associate with PI(3,5)P2-positive late endosomes/lysosomes, and its loss caused lysosomal engorgement and impaired autophagosome clearance, directly connecting biallelic SNX14 mutations to SCAR20 cerebellar ataxia.\",\n      \"evidence\": \"Subcellular fractionation, lipid binding assays, patient-derived fibroblast autophagy flux, zebrafish morphant phenotyping\",\n      \"pmids\": [\"25848753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SNX14 facilitates autophagosome–lysosome fusion was not defined\", \"Whether the lysosomal phenotype is primary or secondary to ER lipid defects was unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining a GPCR signaling regulatory mechanism: SNX14 was shown to act as a dual negative regulator of 5-HT6R signaling—its RGS domain sequesters Gαs to suppress cAMP, while PKA-dependent phosphorylation of SNX14 switches it to promote 5-HT6R internalization and lysosomal degradation, establishing a feedback circuit.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, cAMP measurement, receptor internalization assays, PKA phosphorylation assays, knockdown rescue in HEK293 cells\",\n      \"pmids\": [\"25795301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of 5-HT6R regulation by SNX14 not tested\", \"Whether RGS domain activity extends to other Gα subunits unknown\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Redefining SNX14 as an ER-resident protein: domain mutagenesis established that N-terminal transmembrane helices (not the PX domain) anchor SNX14 to the ER, and SNX14 knockout caused cholesterol and neutral lipid accumulation in lysosomes without disrupting ER–endolysosome contact sites, shifting the primary functional assignment from endosome to ER.\",\n      \"evidence\": \"Domain deletion constructs, filipin staining, cholesterol ester quantification, oleate-induced LD association in SNX14-KO HEK293 cells\",\n      \"pmids\": [\"29635513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ER anchoring not resolved\", \"Whether cholesterol accumulation is a direct lipid transport defect or secondary unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing ER–lipid droplet contact site function: SNX14 was shown to localize to ER–LD contacts in trans following fatty acid treatment, accumulating at ACSL3-positive ER microdomains where nascent LDs bud, and promoting LD maturation/growth independently of Seipin.\",\n      \"evidence\": \"APEX2 proximity labeling, live imaging, topological dissection, KO morphology analysis in U2OS cells\",\n      \"pmids\": [\"30765438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lipid transfer activity not demonstrated\", \"Structural basis of LD binding in trans unknown\", \"Whether SNX14 directly senses nascent LD budding or is passively recruited unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connecting SNX14 to fatty acid desaturation and lipotoxicity: APEX2 proteomics identified SCD1 as a functional partner, and SNX14 loss phenocopied SCD1 impairment by increasing membrane lipid saturation and sensitizing cells to palmitate-induced lipotoxic death—a phenotype rescued by SCD1 overexpression—establishing lipotoxicity as the cellular pathomechanism in SCAR20.\",\n      \"evidence\": \"APEX2 proximity labeling, lipidomic profiling, SCD1 overexpression rescue, lipotoxicity assays in SNX14-KO and SCAR20 patient fibroblasts\",\n      \"pmids\": [\"33310904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNX14 directly modulates SCD1 enzymatic activity or substrate access unknown\", \"Tissue-specific lipotoxic thresholds in Purkinje cells not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealing a microtubule/mitochondrial transport role in neurodegeneration: SNX14 deficiency was found to destabilize spastin, disrupt microtubule organization and axonal mitochondrial transport in Purkinje cells, with valproate rescuing both mitochondrial transport and motor deficits in vivo, adding a cytoskeletal dimension to the SCAR20 mechanism.\",\n      \"evidence\": \"Snx14-deficient mouse model, spastin protein quantification, live axonal mitochondrial transport imaging, valproate treatment rescue\",\n      \"pmids\": [\"34691693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SNX14 stabilizes spastin not defined\", \"Whether spastin destabilization is a direct interaction or mediated by lipid changes unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Validating lipotoxicity as the in vivo Purkinje cell death mechanism: lipidomic and ultrastructural analysis of predegenerating SNX14-deficient cerebella revealed acylcarnitine accumulation, triglyceride depletion, LD content defects, and telolysosome enlargement, confirming that lipid storage failure precedes neurodegeneration.\",\n      \"evidence\": \"SNX14-deficient mouse cerebella, electron microscopy, lipidomic profiling, immunohistochemistry\",\n      \"pmids\": [\"38625743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from lipid storage defect to Purkinje cell death not fully delineated\", \"Contribution of lysosomal versus ER dysfunction not resolved in vivo\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying GluA2 as a neuronal substrate: SNX14 was shown to promote lysosomal degradation of the AMPA receptor subunit GluA2, thereby regulating glutamatergic transmission and seizure susceptibility, expanding its membrane protein trafficking repertoire beyond 5-HT6R.\",\n      \"evidence\": \"SNX14 knockdown and overexpression in mouse hippocampus, GluA2 western blotting, lysosomal inhibition, seizure behavioral assays\",\n      \"pmids\": [\"40237949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SNX14 directly binds GluA2 not shown\", \"Mechanism of cargo selectivity for GluA2 versus other receptors unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include whether SNX14 directly transfers lipids at ER–LD contacts, how it mechanistically couples to SCD1 activity, the structural basis of its multi-site membrane engagement, and whether lipotoxicity and cytoskeletal defects represent parallel or convergent pathogenic pathways in SCAR20.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct lipid transfer activity demonstrated\", \"No high-resolution structure of SNX14\", \"Relative contributions of lipotoxicity versus spastin/microtubule defects to Purkinje cell death unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 3, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [4, 5, 8]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4, 5, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SCD1\", \"ACSL3\", \"HTR6\", \"GNAS\", \"GRIA2\", \"SPAST\"],\n    \"other_free_text\": []\n  }\n}\n```"}