{"gene":"SARS2","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2008,"finding":"Transcription from the bidirectional human MRPS12/SARSM promoter is governed by an array of CCAAT boxes that interact with transcription factor NF-Y, in a manner essentially similar to the mouse promoter. Mitochondrial stress (inhibitors of mitochondrial protein synthesis, uncouplers, or respiratory chain inhibitors) produces two distinct outcomes depending on cell type and conditions: dose-dependent bidirectional transcriptional suppression under prolonged stress (CCAAT-box-dependent), or strong bidirectional stimulation of promoter activity under pre-treatment conditions (independent of the CCAAT box array and putative NRF-2/AP-1 sites), with stimulation correlated to mitochondrial ROS production.","method":"Reporter gene assays with mutated promoter constructs in multiple human and mouse cell lines; treatment with mitochondrial toxins","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assays, mutant constructs, multiple cell lines, pharmacological perturbations) in a single lab","pmids":["18755224"],"is_preprint":false},{"year":2009,"finding":"NF-Y binds the array of four CCAAT boxes in the bidirectional MRPS12/SARSM promoter in two alternate configurations related to directional transcriptional selectivity, influencing relative transcriptional output in the SARSM direction. CCAAT box function is combinatorial but not simply additive; inversion or exchange of individual boxes has minimal effect on directional selectivity. Over-expression of wild-type or dominant-negative NF-Y affected transcription in the SARSM direction only.","method":"EMSA; reporter gene assays with all permutations of CCAAT box mutations; over-expression of wild-type and dominant-negative NF-Y constructs in human and mouse cells","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus multiple mutant reporter constructs, single lab, two orthogonal methods","pmids":["19439209"],"is_preprint":false},{"year":2001,"finding":"Sequencing of the complete coding regions, proximal promoters, 5′ and 3′ UTRs, and splice junctions of SARSM (mitochondrial seryl-tRNA synthetase) in DFNA4-linked deafness families revealed novel polymorphisms but no plausible disease-causing structural mutations, effectively excluding SARSM coding-region mutations as the cause of DFNA4-linked deafness in these families.","method":"Direct sequencing of coding regions, UTRs, and splice junctions in patient families and controls","journal":"Human mutation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single sequencing study, single lab, negative finding (no causal variant identified)","pmids":["11317363"],"is_preprint":false},{"year":2021,"finding":"Compound heterozygous missense variants in SARS2 (c.667G>A/c.1205G>A) cause HUPRA syndrome, demonstrating that loss-of-function of the mitochondrial seryl-tRNA synthetase encoded by SARS2 is sufficient to cause this mitochondrial disease. Bioinformatics and protein structural modelling predict that the c.667G>A variant disrupts protein function, expanding the pathogenic variant spectrum to include compound heterozygous configurations.","method":"Whole-exome sequencing; Sanger sequencing validation; bioinformatics pathogenicity prediction; protein structural modelling","journal":"Molecular genetics & genomic medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case, genetic identification plus computational modelling only, no direct enzymatic assay","pmids":["33751860"],"is_preprint":false},{"year":2022,"finding":"A genomic locus containing SARS2 on chromosome 19 was associated with earlier age at onset in hereditary spastic paraplegia type 4 (SPG4/SPAST). Western blotting in patient lymphocytes showed that the risk allele tends to upregulate SARS2 expression in earlier-onset patients, suggesting that SARS2 overexpression lowers the age of onset and that reducing SARS2 or improving mitochondrial function could be therapeutic.","method":"Genome-wide association study; Western blotting in patient lymphocytes","journal":"Genetics in medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — GWAS plus Western blot correlation, single study, no direct functional validation of SARS2 mechanism in SPG4","pmids":["36056923"],"is_preprint":false},{"year":2026,"finding":"An allelic series of 11 pathogenic SARS2 variants showed variant-dependent effects on mitochondrial oxygen consumption rate, indicating that different pathogenic variants impair mitochondrial function to different degrees. Notably, two exon-13 missense variants (D390G and R402H, including the most common pathogenic variant R402H) did not reduce mitochondrial oxygen consumption but instead reduced exon 13 inclusion in the transcript, indicating loss-of-function via impaired pre-mRNA splicing rather than protein dysfunction.","method":"Oxygen consumption rate assays (mitochondrial function); computational splicing prediction; functional splicing assays for exon inclusion","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (metabolic, splicing) across 11 variants in a single rigorous study","pmids":["42220212"],"is_preprint":false}],"current_model":"SARS2 encodes the mitochondrial seryl-tRNA synthetase whose transcription is bidirectionally co-regulated with MRPS12 via an NF-Y-bound CCAAT box array responsive to mitochondrial oxidative stress; pathogenic loss-of-function variants cause HUPRA syndrome and related mitochondrial diseases through at least two distinct mechanisms—impaired aminoacyl-tRNA charging activity affecting mitochondrial oxygen consumption, or disruption of pre-mRNA splicing that reduces functional transcript levels—with the specific mechanism being variant-dependent."},"narrative":{"mechanistic_narrative":"SARS2 encodes the mitochondrial seryl-tRNA synthetase, an aminoacyl-tRNA charging enzyme required for mitochondrial protein synthesis and respiratory function, whose loss of function causes mitochondrial disease [PMID:33751860, PMID:42220212]. The gene is transcribed from a bidirectional promoter shared with MRPS12 that is controlled by an array of four CCAAT boxes bound by transcription factor NF-Y, which adopts alternate configurations dictating directional transcriptional selectivity toward the SARS2 (SARSM) direction [PMID:18755224, PMID:19439209]. This promoter integrates mitochondrial stress signals: prolonged mitochondrial stress produces dose-dependent, CCAAT-box-dependent bidirectional suppression, whereas pre-treatment conditions drive CCAAT-box-independent stimulation correlated with mitochondrial ROS [PMID:18755224]. Compound heterozygous missense variants in SARS2 cause HUPRA syndrome, establishing that biallelic loss of function of this enzyme is sufficient for disease [PMID:33751860]. Pathogenic variants act through at least two distinct, variant-dependent mechanisms: most impair mitochondrial oxygen consumption to differing degrees, while exon-13 missense variants including the common R402H allele instead reduce exon 13 inclusion during pre-mRNA splicing, causing loss of function without direct protein dysfunction [PMID:42220212].","teleology":[{"year":2001,"claim":"Before SARS2's disease relevance was known, it was tested as a candidate for DFNA4-linked deafness to determine whether coding-region mutations underlie that phenotype; the negative result excluded SARS2 structural mutations as the cause in those families.","evidence":"Direct sequencing of coding regions, UTRs, and splice junctions in deafness families and controls","pmids":["11317363"],"confidence":"Low","gaps":["Negative finding only; does not address SARS2 function","Does not exclude regulatory or non-coding contributions"]},{"year":2008,"claim":"To understand how SARS2 expression is set, the bidirectional MRPS12/SARSM promoter was dissected, establishing that a CCAAT-box array bound by NF-Y governs transcription and that the promoter responds bidirectionally to mitochondrial stress.","evidence":"Reporter gene assays with mutated promoter constructs in multiple human and mouse cell lines under mitochondrial toxin treatment","pmids":["18755224"],"confidence":"Medium","gaps":["Stress responses differ by cell type and timing","Stimulatory response operates independently of the mapped CCAAT/NRF-2/AP-1 sites, leaving its mediator undefined"]},{"year":2009,"claim":"To resolve how a shared promoter achieves directional output, NF-Y binding configurations across the CCAAT array were mapped, showing combinatorial, non-additive control biased toward the SARSM direction.","evidence":"EMSA, permutation reporter constructs, and wild-type/dominant-negative NF-Y overexpression in human and mouse cells","pmids":["19439209"],"confidence":"Medium","gaps":["Mechanistic basis of alternate NF-Y configurations not structurally defined","Connection between directional selectivity and physiological MRPS12:SARS2 stoichiometry untested"]},{"year":2021,"claim":"To extend the pathogenic variant spectrum, compound heterozygous SARS2 variants were identified in a HUPRA syndrome case, demonstrating that biallelic loss of function of the enzyme is sufficient to cause the disease.","evidence":"Whole-exome and Sanger sequencing with bioinformatic and structural pathogenicity prediction","pmids":["33751860"],"confidence":"Low","gaps":["Single case","Variant effect predicted computationally without direct enzymatic assay"]},{"year":2022,"claim":"To test whether SARS2 dosage modifies an unrelated neurodegenerative disease, a chromosome 19 locus containing SARS2 was linked to age at onset in SPG4, with the risk allele correlating with higher SARS2 protein in earlier-onset patients.","evidence":"GWAS plus Western blotting in patient lymphocytes","pmids":["36056923"],"confidence":"Low","gaps":["Correlative; no functional validation that SARS2 levels causally alter SPG4 onset","Locus contains other genes; SARS2 causality not isolated"]},{"year":2026,"claim":"To explain why pathogenic SARS2 variants produce heterogeneous outcomes, an allelic series resolved two distinct loss-of-function mechanisms—graded impairment of mitochondrial respiration versus disrupted exon 13 splicing for the common R402H and D390G alleles.","evidence":"Oxygen consumption rate assays, computational splicing prediction, and functional exon-inclusion splicing assays across 11 variants","pmids":["42220212"],"confidence":"Medium","gaps":["Direct aminoacylation activity not measured per variant","Tissue-specific consequences of splicing defect not characterized"]},{"year":null,"claim":"How SARS2 transcriptional regulation, aminoacylation activity, and splicing fidelity integrate to set tissue-specific disease severity remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the enzyme with its tRNA substrate in the corpus","Link between NF-Y-driven expression level and variant pathogenicity untested","Genotype-phenotype map across HUPRA, SPG4, and other presentations incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[3,5]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["NFYA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NP81","full_name":"Serine--tRNA ligase, mitochondrial","aliases":["SerRSmt","Seryl-tRNA synthetase","SerRS","Seryl-tRNA(Ser/Sec) synthetase"],"length_aa":518,"mass_kda":58.3,"function":"Catalyzes the attachment of serine to tRNA(Ser). Is also probably able to aminoacylate tRNA(Sec) with serine, to form the misacylated tRNA L-seryl-tRNA(Sec), which will be further converted into selenocysteinyl-tRNA(Sec)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q9NP81/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SARS2","classification":"Common Essential","n_dependent_lines":906,"n_total_lines":1208,"dependency_fraction":0.75},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2},{"gene":"SLC25A6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SARS2","total_profiled":1310},"omim":[{"mim_id":"613845","title":"HYPERURICEMIA, PULMONARY HYPERTENSION, RENAL FAILURE, AND ALKALOSIS SYNDROME; HUPRAS","url":"https://www.omim.org/entry/613845"},{"mim_id":"612804","title":"SERYL-tRNA SYNTHETASE 2; SARS2","url":"https://www.omim.org/entry/612804"},{"mim_id":"602557","title":"SPONDYLOEPIMETAPHYSEAL DYSPLASIA, SHOHAT TYPE; SEMDSH","url":"https://www.omim.org/entry/602557"},{"mim_id":"300365","title":"TOLL-LIKE RECEPTOR 7; TLR7","url":"https://www.omim.org/entry/300365"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Mitochondria","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SARS2"},"hgnc":{"alias_symbol":["FLJ20450","mtSerRS","SerRSmt","SARS","SERS","SYS"],"prev_symbol":["SARSM"]},"alphafold":{"accession":"Q9NP81","domains":[{"cath_id":"1.10.287.40","chopping":"54-169","consensus_level":"high","plddt":93.9684,"start":54,"end":169},{"cath_id":"3.30.930.10","chopping":"184-491","consensus_level":"high","plddt":97.2425,"start":184,"end":491}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP81","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP81-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP81-F1-predicted_aligned_error_v6.png","plddt_mean":90.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SARS2","jax_strain_url":"https://www.jax.org/strain/search?query=SARS2"},"sequence":{"accession":"Q9NP81","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NP81.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NP81/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP81"}},"corpus_meta":[{"pmid":"17296929","id":"PMC_17296929","title":"Reciprocal asymmetry of SYS-1/beta-catenin and POP-1/TCF controls asymmetric divisions in Caenorhabditis elegans.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17296929","citation_count":101,"is_preprint":false},{"pmid":"15020416","id":"PMC_15020416","title":"The sys-1 and sys-3 genes cooperate with Wnt signaling to establish the proximal-distal axis of the Caenorhabditis elegans gonad.","date":"2004","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15020416","citation_count":82,"is_preprint":false},{"pmid":"17567664","id":"PMC_17567664","title":"Binary cell fate specification during C. elegans embryogenesis driven by reiterated reciprocal asymmetry of TCF POP-1 and its coactivator beta-catenin SYS-1.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17567664","citation_count":82,"is_preprint":false},{"pmid":"8923208","id":"PMC_8923208","title":"Isolation and characterization of SYS genes from yeast, multicopy suppressors of the functional loss of the transport GTPase Ypt6p.","date":"1996","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/8923208","citation_count":75,"is_preprint":false},{"pmid":"18978022","id":"PMC_18978022","title":"Sys-BodyFluid: a systematical database for human body fluid proteome research.","date":"2008","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/18978022","citation_count":71,"is_preprint":false},{"pmid":"34403466","id":"PMC_34403466","title":"Characterization of SARS2 Nsp15 nuclease activity reveals it's mad about U.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34403466","citation_count":67,"is_preprint":false},{"pmid":"2164218","id":"PMC_2164218","title":"Symplastic spermatids (sys): a recessive insertional mutation in mice causing a defect in spermatogenesis.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2164218","citation_count":65,"is_preprint":false},{"pmid":"33621843","id":"PMC_33621843","title":"Persistent SARS-2 infections contribute to long COVID-19.","date":"2021","source":"Medical hypotheses","url":"https://pubmed.ncbi.nlm.nih.gov/33621843","citation_count":63,"is_preprint":false},{"pmid":"27018016","id":"PMC_27018016","title":"Cohort Profile: The Saguenay Youth Study (SYS).","date":"2017","source":"International journal of epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/27018016","citation_count":53,"is_preprint":false},{"pmid":"11161562","id":"PMC_11161562","title":"The sys-1 gene and sexual dimorphism during gonadogenesis in Caenorhabditis elegans.","date":"2001","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/11161562","citation_count":47,"is_preprint":false},{"pmid":"18477457","id":"PMC_18477457","title":"The C. elegans SYS-1 protein is a bona fide beta-catenin.","date":"2008","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/18477457","citation_count":43,"is_preprint":false},{"pmid":"1759682","id":"PMC_1759682","title":"Testis structure in the sys (symplastic spermatids) mouse.","date":"1991","source":"The American journal of anatomy","url":"https://pubmed.ncbi.nlm.nih.gov/1759682","citation_count":26,"is_preprint":false},{"pmid":"36479439","id":"PMC_36479439","title":"RNA G-quadruplex forming regions from SARS-2, SARS-1 and MERS coronoviruses.","date":"2022","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36479439","citation_count":13,"is_preprint":false},{"pmid":"35893821","id":"PMC_35893821","title":"Intranasal Immunization with a Vaccinia Virus Vaccine Vector Expressing Pre-Fusion Stabilized SARS-CoV-2 Spike Fully Protected Mice against Lethal Challenge with the Heavily Mutated Mouse-Adapted SARS2-N501YMA30 Strain of SARS-CoV-2.","date":"2022","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/35893821","citation_count":13,"is_preprint":false},{"pmid":"18755224","id":"PMC_18755224","title":"Modulation of Mrps12/Sarsm promoter activity in response to mitochondrial stress.","date":"2008","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/18755224","citation_count":12,"is_preprint":false},{"pmid":"19439209","id":"PMC_19439209","title":"NF-Y influences directionality of transcription from the bidirectional Mrps12/Sarsm promoter in both mouse and human cells.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19439209","citation_count":10,"is_preprint":false},{"pmid":"32703328","id":"PMC_32703328","title":"The rationale for a multi-step therapeutic approach based on antivirals, drugs and nutrients with immunomodulatory activity in patients with coronavirus-SARS2-induced disease of different severities.","date":"2020","source":"The British journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/32703328","citation_count":10,"is_preprint":false},{"pmid":"34909775","id":"PMC_34909775","title":"Intranasal immunization with a vaccinia virus vaccine vector expressing pre-fusion stabilized SARS-CoV-2 spike fully protected mice against lethal challenge with the heavily mutated mouse-adapted SARS2-N501Y MA30 strain of SARS-CoV-2.","date":"2021","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/34909775","citation_count":8,"is_preprint":false},{"pmid":"33751860","id":"PMC_33751860","title":"Novel SARS2 variants identified in a Chinese girl with HUPRA syndrome.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33751860","citation_count":7,"is_preprint":false},{"pmid":"11317363","id":"PMC_11317363","title":"Novel coding-region polymorphisms in mitochondrial seryl-tRNA synthetase (SARSM) and mitoribosomal protein S12 (RPMS12) genes in DFNA4 autosomal dominant deafness families.","date":"2001","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/11317363","citation_count":6,"is_preprint":false},{"pmid":"39083418","id":"PMC_39083418","title":"Structural basis for mouse receptor recognition by bat SARS2-like coronaviruses.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39083418","citation_count":5,"is_preprint":false},{"pmid":"34650101","id":"PMC_34650101","title":"Fluorescent glycan fingerprinting of SARS2 spike proteins.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34650101","citation_count":5,"is_preprint":false},{"pmid":"35196020","id":"PMC_35196020","title":"Centrosomal enrichment and proteasomal degradation of SYS-1/β-catenin requires the microtubule motor dynein.","date":"2022","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/35196020","citation_count":4,"is_preprint":false},{"pmid":"36056923","id":"PMC_36056923","title":"The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4.","date":"2022","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36056923","citation_count":4,"is_preprint":false},{"pmid":"34110003","id":"PMC_34110003","title":"Novel method for quantifying cells on carriers and its demonstration during SARS-2 vaccine development.","date":"2021","source":"Biotechnology and 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Sechenova","url":"https://pubmed.ncbi.nlm.nih.gov/26827491","citation_count":3,"is_preprint":false},{"pmid":"32803023","id":"PMC_32803023","title":"Feasibility study of stem-cell enriched autologous lipotransfer to treat oro-facial fibrosis in systemic sclerosis (Sys-Stem): Protocol for open-label randomised controlled trial.","date":"2020","source":"International journal of surgery protocols","url":"https://pubmed.ncbi.nlm.nih.gov/32803023","citation_count":3,"is_preprint":false},{"pmid":"33534852","id":"PMC_33534852","title":"Uncovering potential host proteins and pathways that may interact with eukaryotic short linear motifs in viral proteins of MERS, SARS and SARS2 coronaviruses that infect humans.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33534852","citation_count":2,"is_preprint":false},{"pmid":"38264205","id":"PMC_38264205","title":"Variants in the SARS2 gene cause HUPRA syndrome with atypical features: two case reports and review of the literature.","date":"2023","source":"Oxford medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/38264205","citation_count":1,"is_preprint":false},{"pmid":"40010690","id":"PMC_40010690","title":"Nuclear localization and transactivation of SYS-1/β-catenin is the result of serial gene duplications and subfunctionalizations.","date":"2025","source":"Cells & development","url":"https://pubmed.ncbi.nlm.nih.gov/40010690","citation_count":1,"is_preprint":false},{"pmid":"37503055","id":"PMC_37503055","title":"SYS-1/beta-catenin inheritance and regulation by Wnt-signaling during asymmetric cell division.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37503055","citation_count":0,"is_preprint":false},{"pmid":"39813084","id":"PMC_39813084","title":"SYS-1/beta-catenin inheritance and regulation by Wnt signaling during asymmetric cell division.","date":"2025","source":"Molecular biology of the 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eQTL, and pQTL data.","date":"2025","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41289788","citation_count":0,"is_preprint":false},{"pmid":"41667644","id":"PMC_41667644","title":"Structural basis for bat receptor recognition by SARS-CoV-2 and bat SARS2-like coronaviruses.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41667644","citation_count":0,"is_preprint":false},{"pmid":"42220212","id":"PMC_42220212","title":"Multiple mechanisms lead to loss-of-function effects of SARS2 variants: implications for genotype-phenotype analyses.","date":"2026","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/42220212","citation_count":0,"is_preprint":false},{"pmid":"30640987","id":"PMC_30640987","title":"[Efficacy Observation of Chinese Herbal Fumigation Combined Western Drugs for Treating Sys- temic Sclerosis Complicated Pulmonary Arterial Hypertension].","date":"2016","source":"Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30640987","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.14.607914","title":"SARS-CoV-2 and Mycobacterium tuberculosis co-infection in vitro","date":"2024-08-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.14.607914","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.05.24310017","title":"MENSA, a Media Enriched with Newly Synthesized Antibodies, to Identify SARS-CoV-2 Persistence and Latent Viral Reactivation in Long-COVID","date":"2024-07-07","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.05.24310017","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.03.601941","title":"IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo","date":"2024-07-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.03.601941","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22117,"output_tokens":2062,"usd":0.048641,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8627,"output_tokens":2380,"usd":0.051318,"stage2_stop_reason":"end_turn"},"total_usd":0.099959,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical SARS2 gene (human mitochondrial seryl-tRNA synthetase 2, also known as SARSM, SerRSmt, SYS, mtSerRS).\n\nPapers about the canonical SARS2 gene:\n- PMID:18755224 (Mrps12/Sarsm promoter regulation)\n- PMID:19439209 (NF-Y and Sarsm promoter directionality)\n- PMID:11317363 (SARSM coding region polymorphisms)\n- PMID:33751860 (HUPRA syndrome SARS2 variants)\n- PMID:38264205 (HUPRA syndrome SARS2 variants)\n- PMID:36056923 (SARS2 modifies SPG4 onset)\n- PMID:38326069 (HUPRA syndrome SARS2 missense variants)\n- PMID:42220212 (SARS2 variants mechanisms)\n- PMID:41289788 (Mendelian randomization - expression/eQTL, exclude as no direct mechanism)\n\nPapers that are symbol collisions or off-topic: C. elegans SYS-1/beta-catenin papers (different gene), yeast SYS genes, SARS-CoV-2 papers using \"SARS2\" as abbreviation for the virus, mouse \"sys\" mutation, Saguenay Youth Study, etc.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Transcription from the bidirectional human MRPS12/SARSM promoter is governed by an array of CCAAT boxes that interact with transcription factor NF-Y, in a manner essentially similar to the mouse promoter. Mitochondrial stress (inhibitors of mitochondrial protein synthesis, uncouplers, or respiratory chain inhibitors) produces two distinct outcomes depending on cell type and conditions: dose-dependent bidirectional transcriptional suppression under prolonged stress (CCAAT-box-dependent), or strong bidirectional stimulation of promoter activity under pre-treatment conditions (independent of the CCAAT box array and putative NRF-2/AP-1 sites), with stimulation correlated to mitochondrial ROS production.\",\n      \"method\": \"Reporter gene assays with mutated promoter constructs in multiple human and mouse cell lines; treatment with mitochondrial toxins\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assays, mutant constructs, multiple cell lines, pharmacological perturbations) in a single lab\",\n      \"pmids\": [\"18755224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NF-Y binds the array of four CCAAT boxes in the bidirectional MRPS12/SARSM promoter in two alternate configurations related to directional transcriptional selectivity, influencing relative transcriptional output in the SARSM direction. CCAAT box function is combinatorial but not simply additive; inversion or exchange of individual boxes has minimal effect on directional selectivity. Over-expression of wild-type or dominant-negative NF-Y affected transcription in the SARSM direction only.\",\n      \"method\": \"EMSA; reporter gene assays with all permutations of CCAAT box mutations; over-expression of wild-type and dominant-negative NF-Y constructs in human and mouse cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus multiple mutant reporter constructs, single lab, two orthogonal methods\",\n      \"pmids\": [\"19439209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sequencing of the complete coding regions, proximal promoters, 5′ and 3′ UTRs, and splice junctions of SARSM (mitochondrial seryl-tRNA synthetase) in DFNA4-linked deafness families revealed novel polymorphisms but no plausible disease-causing structural mutations, effectively excluding SARSM coding-region mutations as the cause of DFNA4-linked deafness in these families.\",\n      \"method\": \"Direct sequencing of coding regions, UTRs, and splice junctions in patient families and controls\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single sequencing study, single lab, negative finding (no causal variant identified)\",\n      \"pmids\": [\"11317363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Compound heterozygous missense variants in SARS2 (c.667G>A/c.1205G>A) cause HUPRA syndrome, demonstrating that loss-of-function of the mitochondrial seryl-tRNA synthetase encoded by SARS2 is sufficient to cause this mitochondrial disease. Bioinformatics and protein structural modelling predict that the c.667G>A variant disrupts protein function, expanding the pathogenic variant spectrum to include compound heterozygous configurations.\",\n      \"method\": \"Whole-exome sequencing; Sanger sequencing validation; bioinformatics pathogenicity prediction; protein structural modelling\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case, genetic identification plus computational modelling only, no direct enzymatic assay\",\n      \"pmids\": [\"33751860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A genomic locus containing SARS2 on chromosome 19 was associated with earlier age at onset in hereditary spastic paraplegia type 4 (SPG4/SPAST). Western blotting in patient lymphocytes showed that the risk allele tends to upregulate SARS2 expression in earlier-onset patients, suggesting that SARS2 overexpression lowers the age of onset and that reducing SARS2 or improving mitochondrial function could be therapeutic.\",\n      \"method\": \"Genome-wide association study; Western blotting in patient lymphocytes\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — GWAS plus Western blot correlation, single study, no direct functional validation of SARS2 mechanism in SPG4\",\n      \"pmids\": [\"36056923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"An allelic series of 11 pathogenic SARS2 variants showed variant-dependent effects on mitochondrial oxygen consumption rate, indicating that different pathogenic variants impair mitochondrial function to different degrees. Notably, two exon-13 missense variants (D390G and R402H, including the most common pathogenic variant R402H) did not reduce mitochondrial oxygen consumption but instead reduced exon 13 inclusion in the transcript, indicating loss-of-function via impaired pre-mRNA splicing rather than protein dysfunction.\",\n      \"method\": \"Oxygen consumption rate assays (mitochondrial function); computational splicing prediction; functional splicing assays for exon inclusion\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (metabolic, splicing) across 11 variants in a single rigorous study\",\n      \"pmids\": [\"42220212\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SARS2 encodes the mitochondrial seryl-tRNA synthetase whose transcription is bidirectionally co-regulated with MRPS12 via an NF-Y-bound CCAAT box array responsive to mitochondrial oxidative stress; pathogenic loss-of-function variants cause HUPRA syndrome and related mitochondrial diseases through at least two distinct mechanisms—impaired aminoacyl-tRNA charging activity affecting mitochondrial oxygen consumption, or disruption of pre-mRNA splicing that reduces functional transcript levels—with the specific mechanism being variant-dependent.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SARS2 encodes the mitochondrial seryl-tRNA synthetase, an aminoacyl-tRNA charging enzyme required for mitochondrial protein synthesis and respiratory function, whose loss of function causes mitochondrial disease [#3, #5]. The gene is transcribed from a bidirectional promoter shared with MRPS12 that is controlled by an array of four CCAAT boxes bound by transcription factor NF-Y, which adopts alternate configurations dictating directional transcriptional selectivity toward the SARS2 (SARSM) direction [#0, #1]. This promoter integrates mitochondrial stress signals: prolonged mitochondrial stress produces dose-dependent, CCAAT-box-dependent bidirectional suppression, whereas pre-treatment conditions drive CCAAT-box-independent stimulation correlated with mitochondrial ROS [#0]. Compound heterozygous missense variants in SARS2 cause HUPRA syndrome, establishing that biallelic loss of function of this enzyme is sufficient for disease [#3]. Pathogenic variants act through at least two distinct, variant-dependent mechanisms: most impair mitochondrial oxygen consumption to differing degrees, while exon-13 missense variants including the common R402H allele instead reduce exon 13 inclusion during pre-mRNA splicing, causing loss of function without direct protein dysfunction [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Before SARS2's disease relevance was known, it was tested as a candidate for DFNA4-linked deafness to determine whether coding-region mutations underlie that phenotype; the negative result excluded SARS2 structural mutations as the cause in those families.\",\n      \"evidence\": \"Direct sequencing of coding regions, UTRs, and splice junctions in deafness families and controls\",\n      \"pmids\": [\"11317363\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Negative finding only; does not address SARS2 function\", \"Does not exclude regulatory or non-coding contributions\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"To understand how SARS2 expression is set, the bidirectional MRPS12/SARSM promoter was dissected, establishing that a CCAAT-box array bound by NF-Y governs transcription and that the promoter responds bidirectionally to mitochondrial stress.\",\n      \"evidence\": \"Reporter gene assays with mutated promoter constructs in multiple human and mouse cell lines under mitochondrial toxin treatment\",\n      \"pmids\": [\"18755224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stress responses differ by cell type and timing\", \"Stimulatory response operates independently of the mapped CCAAT/NRF-2/AP-1 sites, leaving its mediator undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"To resolve how a shared promoter achieves directional output, NF-Y binding configurations across the CCAAT array were mapped, showing combinatorial, non-additive control biased toward the SARSM direction.\",\n      \"evidence\": \"EMSA, permutation reporter constructs, and wild-type/dominant-negative NF-Y overexpression in human and mouse cells\",\n      \"pmids\": [\"19439209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of alternate NF-Y configurations not structurally defined\", \"Connection between directional selectivity and physiological MRPS12:SARS2 stoichiometry untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"To extend the pathogenic variant spectrum, compound heterozygous SARS2 variants were identified in a HUPRA syndrome case, demonstrating that biallelic loss of function of the enzyme is sufficient to cause the disease.\",\n      \"evidence\": \"Whole-exome and Sanger sequencing with bioinformatic and structural pathogenicity prediction\",\n      \"pmids\": [\"33751860\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single case\", \"Variant effect predicted computationally without direct enzymatic assay\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"To test whether SARS2 dosage modifies an unrelated neurodegenerative disease, a chromosome 19 locus containing SARS2 was linked to age at onset in SPG4, with the risk allele correlating with higher SARS2 protein in earlier-onset patients.\",\n      \"evidence\": \"GWAS plus Western blotting in patient lymphocytes\",\n      \"pmids\": [\"36056923\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative; no functional validation that SARS2 levels causally alter SPG4 onset\", \"Locus contains other genes; SARS2 causality not isolated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"To explain why pathogenic SARS2 variants produce heterogeneous outcomes, an allelic series resolved two distinct loss-of-function mechanisms—graded impairment of mitochondrial respiration versus disrupted exon 13 splicing for the common R402H and D390G alleles.\",\n      \"evidence\": \"Oxygen consumption rate assays, computational splicing prediction, and functional exon-inclusion splicing assays across 11 variants\",\n      \"pmids\": [\"42220212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct aminoacylation activity not measured per variant\", \"Tissue-specific consequences of splicing defect not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SARS2 transcriptional regulation, aminoacylation activity, and splicing fidelity integrate to set tissue-specific disease severity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the enzyme with its tRNA substrate in the corpus\", \"Link between NF-Y-driven expression level and variant pathogenicity untested\", \"Genotype-phenotype map across HUPRA, SPG4, and other presentations incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NFYA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}