{"gene":"UNC80","run_date":"2026-04-28T21:43:01","timeline":{"discoveries":[{"year":2008,"finding":"UNC-80 (C. elegans ortholog) is required for proper localization of NCA-1 and NCA-2 ion channel subunits along axons at non-synaptic regions, and is itself enriched at non-synaptic regions; loss of UNC-80 reduces synaptic calcium transients and neuromuscular junction transmission","method":"C. elegans genetics (loss-of-function mutants), in vivo calcium imaging, immunolocalization","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetics, calcium imaging, localization) in a well-characterized ortholog system","pmids":["18336069"],"is_preprint":false},{"year":2007,"finding":"UNC-80 (C. elegans) encodes a novel conserved neuronal protein required for proper localization of NCA-1 and NCA-2 ion channel subunits; loss of unc-80 partially suppresses synaptojanin mutant locomotory and vesicle depletion defects, placing UNC-80/NCA channels downstream of PIP2 during synaptic vesicle recycling","method":"C. elegans suppressor screen, genetic epistasis, immunolocalization","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with suppressor screen and localization experiments, replicated across two labs","pmids":["17825559"],"is_preprint":false},{"year":2008,"finding":"UNC-80 is a component of the NALCN channel complex required for activation of NALCN by substance P and neurotensin; activation by substance P through TACR1 occurs via a G-protein-independent mechanism requiring Src family kinases and UNC-80","method":"Electrophysiology in hippocampal and VTA neurons, pharmacological dissection of G-protein vs. Src kinase pathways","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — electrophysiology with pharmacological and genetic dissection in native neurons, high citation count indicating broad acceptance","pmids":["19092807"],"is_preprint":false},{"year":2009,"finding":"UNC80 binds Src kinases and recruits Src into the NALCN channel complex, functioning as a scaffold for Src kinases to enable G-protein-independent activation of NALCN by substance P","method":"Co-immunoprecipitation, pulldown assays","journal":"Channels","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP/pulldown, single lab, but mechanistically coherent with prior electrophysiology data","pmids":["19535918"],"is_preprint":false},{"year":2010,"finding":"UNC80 bridges NALCN to UNC79 within the same channel complex; this UNC79-UNC80-NALCN complex is required for the coupling between extracellular Ca2+ sensing (via a Ca2+-sensing GPCR and G-proteins) and NALCN-dependent Na+-leak current activation; the last amino acid of NALCN's intracellular tail is also required","method":"Electrophysiology in cultured hippocampal neurons from nalcn and unc79 knockout mice, pharmacological G-protein manipulation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse electrophysiology with pharmacological dissection, replicated finding, high citation count","pmids":["21040849"],"is_preprint":false},{"year":2013,"finding":"Drosophila UNC80 forms a complex with NARROW ABDOMEN (NALCN ortholog) and UNC79 in the brain; loss of unc80 leads to decreased expression of all three proteins (NA, UNC79, UNC80) post-transcriptionally; UNC80 and UNC79 have functional requirements in circadian pacemaker neurons beyond merely promoting channel subunit expression","method":"Immunoprecipitation from Drosophila brain, loss-of-function genetics, tissue-specific RNAi/rescue, western blotting","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus genetic rescue experiments in Drosophila ortholog system with multiple orthogonal methods","pmids":["24223770"],"is_preprint":false},{"year":2015,"finding":"A truncating UNC80 mutation (p.R51*) in humans abolishes NALCN-dependent basal Na+ leak conductance in neurons, causing a syndrome of hypotonia, severe intellectual disability, and dyskinesia phenotypically similar to NALCN mutations, confirming UNC80's essential role in NALCN function in vivo","method":"Whole exome sequencing, Sanger sequencing, genetic linkage; functional inference from NALCN channel physiology","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — human genetics with loss-of-function allele, no direct channel recording in patient cells","pmids":["26545877"],"is_preprint":false},{"year":2015,"finding":"UNC80 p.Pro1700Ser missense mutation markedly decreases NALCN channel currents in HEK293T cells, demonstrating that UNC80 is required for NALCN channel activity; UNC80 is established as a large component of the NALCN sodium-leak channel complex","method":"Electrophysiology (patch clamp) in HEK293T cells transfected with mutant UNC80 expression plasmid","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 — direct electrophysiological measurement of channel currents with disease-associated mutant in heterologous expression system","pmids":["26708751"],"is_preprint":false},{"year":2020,"finding":"UNC80 and UNC79 are bona fide subunits of the NALCN complex; the C-terminus of UNC80 contains a domain that interacts with UNC79 and contains a signal that overcomes soma-retention to achieve dendritic localization of the complex; UNC80 lacking this C-terminal domain still supports whole-cell NALCN currents but fails to localize to dendrites, demonstrating a role for UNC80 in regulating dendritic membrane potential; UNC80 knockout mice are neonatal lethal","method":"Co-immunoprecipitation, electrophysiology, live imaging/immunofluorescence localization in neurons, UNC80 knockout mouse generation, domain deletion analysis with patient-derived mutations","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including Co-IP, electrophysiology, localization, and KO mouse with specific phenotypic readouts in a single study","pmids":["32620897"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex reveals that UNC79-UNC80 form a large piler-shaped heterodimer tethered to the intracellular side of NALCN through tripartite interactions with NALCN's cytoplasmic loops; two of these interactions are essential for NALCN cell-surface localization; a third interaction relieves NALCN self-inhibition by pulling the auto-inhibitory CTD Interacting Helix (CIH) out of its binding site","method":"Cryo-EM structure determination with functional validation of localization and channel activity","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution cryo-EM structure with functional validation of key interactions","pmids":["35550517"],"is_preprint":false},{"year":2024,"finding":"Unc80 undergoes ADAR2-dependent A-to-I RNA editing exclusively in the brain; mice with gain-of-editing variant (Unc80G/G) show heightened basal neuronal activity in olfactory regions and increased glutamate levels in olfactory bulbs compared to loss-of-editing mice; Unc80 deficiency and loss-of-editing both alter olfactory behavioral responses","method":"CRISPR/Cas9 knock-in mouse models, neuronal activity measurements, glutamate quantification, behavioral analysis, transcriptomics","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR knock-in models with multiple readouts, single lab study","pmids":["38892173"],"is_preprint":false}],"current_model":"UNC80 is a large cytoplasmic auxiliary subunit of the NALCN sodium-leak channel complex (together with UNC79, FAM155A, and NALCN) that forms a piler-shaped heterodimer with UNC79, tethers to NALCN's intracellular loops to relieve NALCN self-inhibition and promote its cell-surface and dendritic localization, scaffolds Src kinases to enable G-protein-independent channel activation by neuropeptides such as substance P, and is required for NALCN-dependent Na⁺-leak current that controls neuronal resting membrane potential and excitability."},"narrative":{"teleology":[{"year":2007,"claim":"Identification of UNC-80 as a novel conserved neuronal protein required for proper axonal localization of NCA/NALCN channels established it as a channel-associated factor rather than a generic neuronal protein.","evidence":"C. elegans suppressor screen, genetic epistasis with synaptojanin, and immunolocalization of NCA-1/NCA-2","pmids":["17825559"],"confidence":"High","gaps":["Biochemical interaction with NCA channels not yet demonstrated","Mechanism of localization control unknown","Mammalian relevance unconfirmed"]},{"year":2008,"claim":"Demonstration that UNC-80 is required for substance P- and neurotensin-induced NALCN activation via a G-protein-independent, Src-kinase-dependent pathway established UNC80 as a signaling scaffold within the channel complex, not merely a trafficking factor.","evidence":"Electrophysiology in hippocampal and VTA neurons with pharmacological dissection of G-protein versus Src kinase pathways; C. elegans calcium imaging and localization","pmids":["19092807","18336069"],"confidence":"High","gaps":["Direct physical interaction between UNC80 and Src not yet shown","Structural basis of scaffold function unknown"]},{"year":2009,"claim":"Biochemical evidence that UNC80 directly binds Src kinases and recruits them into the NALCN complex confirmed the scaffold model for G-protein-independent neuropeptide signaling.","evidence":"Co-immunoprecipitation and pulldown assays","pmids":["19535918"],"confidence":"Medium","gaps":["Single Co-IP/pulldown from one lab without reciprocal validation in native tissue","Binding domain on UNC80 not mapped","Stoichiometry of Src within the complex unknown"]},{"year":2010,"claim":"Establishing that UNC80 bridges NALCN to UNC79 within the same complex and that this trimeric assembly is required for Ca²⁺-sensing-dependent Na⁺-leak current activation defined UNC80 as a central organizer coupling diverse extracellular signals to NALCN gating.","evidence":"Electrophysiology in cultured hippocampal neurons from nalcn and unc79 knockout mice with pharmacological G-protein manipulation","pmids":["21040849"],"confidence":"High","gaps":["Structural basis of UNC79–UNC80 interaction unknown","How UNC80 couples to Ca²⁺-sensing GPCR signaling mechanistically unclear"]},{"year":2013,"claim":"Reciprocal co-IP in Drosophila brain confirmed conserved complex formation and revealed that loss of UNC80 causes post-transcriptional degradation of all three subunits, indicating UNC80 stabilizes the complex beyond merely trafficking the channel.","evidence":"Immunoprecipitation from Drosophila brain, tissue-specific RNAi/rescue, western blotting","pmids":["24223770"],"confidence":"High","gaps":["Degradation pathway of unassembled subunits not identified","Functional roles of UNC80 and UNC79 in circadian neurons beyond expression not defined"]},{"year":2015,"claim":"Human genetic studies linked UNC80 loss-of-function and missense mutations to a neurodevelopmental syndrome and directly demonstrated that patient-derived mutations abolish NALCN currents, confirming UNC80's essential role in human NALCN channel function.","evidence":"Whole-exome sequencing with Sanger validation (p.R51*); patch-clamp electrophysiology of p.Pro1700Ser in HEK293T cells","pmids":["26545877","26708751"],"confidence":"High","gaps":["No channel recordings from patient-derived neurons","Genotype–phenotype correlation across mutation spectrum incomplete"]},{"year":2020,"claim":"Domain-dissection studies revealed that UNC80's C-terminus mediates UNC79 interaction and contains a dendritic targeting signal separable from its channel-activating function, establishing that UNC80 independently regulates subcellular distribution of the NALCN complex.","evidence":"Co-IP, electrophysiology, live imaging in neurons, UNC80 knockout mice (neonatal lethal), domain deletion with patient mutations","pmids":["32620897"],"confidence":"High","gaps":["Molecular identity of dendritic targeting signal not mapped to residues","How dendritic versus somatic NALCN pools differentially affect excitability not quantified"]},{"year":2022,"claim":"The cryo-EM structure of the quaternary NALCN–FAM155A–UNC79–UNC80 complex resolved how UNC79–UNC80 form a piler-shaped heterodimer anchored to NALCN via three intracellular-loop contacts, two promoting surface expression and one relieving autoinhibition by displacing the CIH, providing a complete structural mechanism for UNC80-dependent channel activation.","evidence":"Cryo-EM structure determination with mutagenesis-based functional validation of localization and channel activity","pmids":["35550517"],"confidence":"High","gaps":["Conformational changes during channel gating not captured","How Src kinase docks onto the structurally resolved complex remains unmodeled","Structure determined in detergent — lipid bilayer context missing"]},{"year":2024,"claim":"Discovery that Unc80 mRNA undergoes brain-specific ADAR2-dependent A-to-I RNA editing that modulates basal neuronal activity and glutamate levels in olfactory circuits introduced post-transcriptional regulation of UNC80 as a mechanism tuning channel complex function.","evidence":"CRISPR knock-in mouse models (gain- and loss-of-editing), neuronal activity measurements, glutamate quantification, behavioral assays","pmids":["38892173"],"confidence":"Medium","gaps":["Edited residue's effect on UNC80 protein structure/function not determined","Single lab study awaiting independent replication","Whether editing alters NALCN current directly not tested electrophysiologically"]},{"year":null,"claim":"Key unresolved questions include how Src kinase docks onto the structurally resolved NALCN–UNC80 complex, the identity of the dendritic targeting motif at residue-level resolution, and whether RNA editing of UNC80 directly modulates NALCN channel biophysics.","evidence":"","pmids":[],"confidence":"Low","gaps":["Src binding site on UNC80 not structurally mapped","Dendritic targeting signal not mapped to specific residues","Functional consequence of RNA editing on NALCN currents not tested electrophysiologically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,4,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,8,9]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,4,8]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,4,7,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]}],"complexes":["NALCN–FAM155A–UNC79–UNC80 channel complex"],"partners":["NALCN","UNC79","FAM155A","SRC"],"other_free_text":[]},"mechanistic_narrative":"UNC80 is an essential auxiliary subunit of the NALCN sodium-leak channel complex that scaffolds signaling components and controls channel trafficking, activity, and neuronal excitability. UNC80 forms a large piler-shaped heterodimer with UNC79 that tethers to NALCN's intracellular loops via tripartite interactions: two contacts are required for NALCN cell-surface localization, and a third relieves NALCN autoinhibition by displacing the C-terminal Interacting Helix, thereby activating Na⁺-leak current [PMID:35550517, PMID:32620897]. UNC80 also recruits Src family kinases to enable G-protein-independent activation of NALCN by neuropeptides such as substance P, and its C-terminal domain directs dendritic localization of the channel complex to regulate local membrane potential [PMID:19092807, PMID:19535918, PMID:32620897]. Loss-of-function mutations in human UNC80 cause a syndrome of hypotonia, severe intellectual disability, and dyskinesia, and Unc80-knockout mice are neonatal lethal [PMID:26545877, PMID:26708751, PMID:32620897]."},"prefetch_data":{"uniprot":{"accession":"Q8N2C7","full_name":"Protein unc-80 homolog","aliases":[],"length_aa":3258,"mass_kda":363.4,"function":"Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability (By similarity). Activated by neuropeptides substance P, neurotensin, and extracellular Ca(2+) that regulates neuronal excitability by controlling the sizes of NALCN-dependent sodium-leak current. UNC80 is essential for NALCN sensitivity to extracellular Ca(2+) (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8N2C7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UNC80","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UNC80","total_profiled":1310},"omim":[{"mim_id":"616884","title":"UNC79 HOMOLOG, NALCN CHANNEL COMPLEX SUBUNIT; UNC79","url":"https://www.omim.org/entry/616884"},{"mim_id":"616801","title":"HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION AND CHARACTERISTIC FACIES 2; IHPRF2","url":"https://www.omim.org/entry/616801"},{"mim_id":"615419","title":"HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION AND CHARACTERISTIC FACIES 1; IHPRF1","url":"https://www.omim.org/entry/615419"},{"mim_id":"612636","title":"UNC80 HOMOLOG, NALCN CHANNEL COMPLEX SUBUNIT; UNC80","url":"https://www.omim.org/entry/612636"},{"mim_id":"611549","title":"SODIUM LEAK CHANNEL, NONSELECTIVE; NALCN","url":"https://www.omim.org/entry/611549"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":29.7},{"tissue":"pituitary gland","ntpm":12.8},{"tissue":"retina","ntpm":17.6}],"url":"https://www.proteinatlas.org/search/UNC80"},"hgnc":{"alias_symbol":["FLJ33496","KIAA1843","UNC-80"],"prev_symbol":["C2orf21"]},"alphafold":{"accession":"Q8N2C7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N2C7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N2C7-6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N2C7-6-F1-predicted_aligned_error_v6.png","plddt_mean":73.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UNC80","jax_strain_url":"https://www.jax.org/strain/search?query=UNC80"},"sequence":{"accession":"Q8N2C7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N2C7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N2C7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N2C7"}},"corpus_meta":[{"pmid":"21040849","id":"PMC_21040849","title":"Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex.","date":"2010","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/21040849","citation_count":162,"is_preprint":false},{"pmid":"19092807","id":"PMC_19092807","title":"Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/19092807","citation_count":130,"is_preprint":false},{"pmid":"18336069","id":"PMC_18336069","title":"A putative cation channel, NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans.","date":"2008","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/18336069","citation_count":99,"is_preprint":false},{"pmid":"17825559","id":"PMC_17825559","title":"UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants.","date":"2007","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/17825559","citation_count":74,"is_preprint":false},{"pmid":"26545877","id":"PMC_26545877","title":"UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN.","date":"2015","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26545877","citation_count":42,"is_preprint":false},{"pmid":"26708751","id":"PMC_26708751","title":"Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26708751","citation_count":42,"is_preprint":false},{"pmid":"30167850","id":"PMC_30167850","title":"Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).","date":"2018","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30167850","citation_count":40,"is_preprint":false},{"pmid":"26708753","id":"PMC_26708753","title":"Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26708753","citation_count":38,"is_preprint":false},{"pmid":"24223770","id":"PMC_24223770","title":"UNC79 and UNC80, putative auxiliary subunits of the NARROW ABDOMEN ion channel, are indispensable for robust circadian locomotor rhythms in Drosophila.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24223770","citation_count":37,"is_preprint":false},{"pmid":"35550517","id":"PMC_35550517","title":"Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35550517","citation_count":26,"is_preprint":false},{"pmid":"19535918","id":"PMC_19535918","title":"UNC80 functions as a scaffold for Src kinases in NALCN channel function.","date":"2009","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19535918","citation_count":24,"is_preprint":false},{"pmid":"32620897","id":"PMC_32620897","title":"Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32620897","citation_count":22,"is_preprint":false},{"pmid":"30771478","id":"PMC_30771478","title":"Whole exome sequencing revealed mutations in FBXL4, UNC80, and ADK in Thai patients with severe intellectual disabilities.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30771478","citation_count":14,"is_preprint":false},{"pmid":"29430593","id":"PMC_29430593","title":"Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2).","date":"2018","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/29430593","citation_count":13,"is_preprint":false},{"pmid":"34594366","id":"PMC_34594366","title":"Case Report: Complete Maternal Uniparental Disomy of Chromosome 2 With a Novel UNC80 Splicing Variant c.5609-4G> A in a Chinese Patient With Infantile Hypotonia With Psychomotor Retardation and Characteristic Facies 2.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34594366","citation_count":7,"is_preprint":false},{"pmid":"37067163","id":"PMC_37067163","title":"Novel nonsense mutation in UNC80 in a Turkish patient further validates the sociable skill and severe gastrointestinal problems as part of disease spectrum.","date":"2023","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/37067163","citation_count":4,"is_preprint":false},{"pmid":"31223553","id":"PMC_31223553","title":"Atypical Presentation of Viral Gastroenteritis in a Three-year-old Child Due to a UNC80 Mutation.","date":"2019","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/31223553","citation_count":4,"is_preprint":false},{"pmid":"30092901","id":"PMC_30092901","title":"Case Report of Pediatric Channelopathies With UNC80 and KCNJ11 Mutations Having Abnormal Respiratory Control Treated With Positive Airway Pressure Therapy.","date":"2018","source":"Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30092901","citation_count":4,"is_preprint":false},{"pmid":"38892173","id":"PMC_38892173","title":"Imbalance in Unc80 RNA Editing Disrupts Dynamic Neuronal Activity and Olfactory Perception.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38892173","citation_count":1,"is_preprint":false},{"pmid":"41458659","id":"PMC_41458659","title":"Clinical Utility of Whole-Exome Sequencing in a Consanguineous Family with UNC80-related Neurodevelopmental Disorder: A Case Series and Review of the Literature.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/41458659","citation_count":0,"is_preprint":false},{"pmid":"40801661","id":"PMC_40801661","title":"Integrated Genomic Approach: A Five Exon Intragenic Deletion in UNC80 Combines With a Novel Splice Variant to Cause IHPRF2 Syndrome in an Italian Family.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/40801661","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.04.647097","title":"NALCN/Cch1 channelosome subunits originated in early eukaryotes and are fully conserved in animals, fungi, and apusomonads","date":"2025-04-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.04.647097","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10705,"output_tokens":2616,"usd":0.035678},"stage2":{"model":"claude-opus-4-6","input_tokens":5941,"output_tokens":2515,"usd":0.13887},"total_usd":0.174548,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"UNC-80 (C. elegans ortholog) is required for proper localization of NCA-1 and NCA-2 ion channel subunits along axons at non-synaptic regions, and is itself enriched at non-synaptic regions; loss of UNC-80 reduces synaptic calcium transients and neuromuscular junction transmission\",\n      \"method\": \"C. elegans genetics (loss-of-function mutants), in vivo calcium imaging, immunolocalization\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, calcium imaging, localization) in a well-characterized ortholog system\",\n      \"pmids\": [\"18336069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UNC-80 (C. elegans) encodes a novel conserved neuronal protein required for proper localization of NCA-1 and NCA-2 ion channel subunits; loss of unc-80 partially suppresses synaptojanin mutant locomotory and vesicle depletion defects, placing UNC-80/NCA channels downstream of PIP2 during synaptic vesicle recycling\",\n      \"method\": \"C. elegans suppressor screen, genetic epistasis, immunolocalization\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with suppressor screen and localization experiments, replicated across two labs\",\n      \"pmids\": [\"17825559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UNC-80 is a component of the NALCN channel complex required for activation of NALCN by substance P and neurotensin; activation by substance P through TACR1 occurs via a G-protein-independent mechanism requiring Src family kinases and UNC-80\",\n      \"method\": \"Electrophysiology in hippocampal and VTA neurons, pharmacological dissection of G-protein vs. Src kinase pathways\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology with pharmacological and genetic dissection in native neurons, high citation count indicating broad acceptance\",\n      \"pmids\": [\"19092807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UNC80 binds Src kinases and recruits Src into the NALCN channel complex, functioning as a scaffold for Src kinases to enable G-protein-independent activation of NALCN by substance P\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays\",\n      \"journal\": \"Channels\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/pulldown, single lab, but mechanistically coherent with prior electrophysiology data\",\n      \"pmids\": [\"19535918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UNC80 bridges NALCN to UNC79 within the same channel complex; this UNC79-UNC80-NALCN complex is required for the coupling between extracellular Ca2+ sensing (via a Ca2+-sensing GPCR and G-proteins) and NALCN-dependent Na+-leak current activation; the last amino acid of NALCN's intracellular tail is also required\",\n      \"method\": \"Electrophysiology in cultured hippocampal neurons from nalcn and unc79 knockout mice, pharmacological G-protein manipulation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse electrophysiology with pharmacological dissection, replicated finding, high citation count\",\n      \"pmids\": [\"21040849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila UNC80 forms a complex with NARROW ABDOMEN (NALCN ortholog) and UNC79 in the brain; loss of unc80 leads to decreased expression of all three proteins (NA, UNC79, UNC80) post-transcriptionally; UNC80 and UNC79 have functional requirements in circadian pacemaker neurons beyond merely promoting channel subunit expression\",\n      \"method\": \"Immunoprecipitation from Drosophila brain, loss-of-function genetics, tissue-specific RNAi/rescue, western blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus genetic rescue experiments in Drosophila ortholog system with multiple orthogonal methods\",\n      \"pmids\": [\"24223770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A truncating UNC80 mutation (p.R51*) in humans abolishes NALCN-dependent basal Na+ leak conductance in neurons, causing a syndrome of hypotonia, severe intellectual disability, and dyskinesia phenotypically similar to NALCN mutations, confirming UNC80's essential role in NALCN function in vivo\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, genetic linkage; functional inference from NALCN channel physiology\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — human genetics with loss-of-function allele, no direct channel recording in patient cells\",\n      \"pmids\": [\"26545877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UNC80 p.Pro1700Ser missense mutation markedly decreases NALCN channel currents in HEK293T cells, demonstrating that UNC80 is required for NALCN channel activity; UNC80 is established as a large component of the NALCN sodium-leak channel complex\",\n      \"method\": \"Electrophysiology (patch clamp) in HEK293T cells transfected with mutant UNC80 expression plasmid\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct electrophysiological measurement of channel currents with disease-associated mutant in heterologous expression system\",\n      \"pmids\": [\"26708751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UNC80 and UNC79 are bona fide subunits of the NALCN complex; the C-terminus of UNC80 contains a domain that interacts with UNC79 and contains a signal that overcomes soma-retention to achieve dendritic localization of the complex; UNC80 lacking this C-terminal domain still supports whole-cell NALCN currents but fails to localize to dendrites, demonstrating a role for UNC80 in regulating dendritic membrane potential; UNC80 knockout mice are neonatal lethal\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology, live imaging/immunofluorescence localization in neurons, UNC80 knockout mouse generation, domain deletion analysis with patient-derived mutations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including Co-IP, electrophysiology, localization, and KO mouse with specific phenotypic readouts in a single study\",\n      \"pmids\": [\"32620897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex reveals that UNC79-UNC80 form a large piler-shaped heterodimer tethered to the intracellular side of NALCN through tripartite interactions with NALCN's cytoplasmic loops; two of these interactions are essential for NALCN cell-surface localization; a third interaction relieves NALCN self-inhibition by pulling the auto-inhibitory CTD Interacting Helix (CIH) out of its binding site\",\n      \"method\": \"Cryo-EM structure determination with functional validation of localization and channel activity\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution cryo-EM structure with functional validation of key interactions\",\n      \"pmids\": [\"35550517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Unc80 undergoes ADAR2-dependent A-to-I RNA editing exclusively in the brain; mice with gain-of-editing variant (Unc80G/G) show heightened basal neuronal activity in olfactory regions and increased glutamate levels in olfactory bulbs compared to loss-of-editing mice; Unc80 deficiency and loss-of-editing both alter olfactory behavioral responses\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse models, neuronal activity measurements, glutamate quantification, behavioral analysis, transcriptomics\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR knock-in models with multiple readouts, single lab study\",\n      \"pmids\": [\"38892173\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UNC80 is a large cytoplasmic auxiliary subunit of the NALCN sodium-leak channel complex (together with UNC79, FAM155A, and NALCN) that forms a piler-shaped heterodimer with UNC79, tethers to NALCN's intracellular loops to relieve NALCN self-inhibition and promote its cell-surface and dendritic localization, scaffolds Src kinases to enable G-protein-independent channel activation by neuropeptides such as substance P, and is required for NALCN-dependent Na⁺-leak current that controls neuronal resting membrane potential and excitability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"UNC80 is an essential auxiliary subunit of the NALCN sodium-leak channel complex that scaffolds signaling components and controls channel trafficking, activity, and neuronal excitability. UNC80 forms a large piler-shaped heterodimer with UNC79 that tethers to NALCN's intracellular loops via tripartite interactions: two contacts are required for NALCN cell-surface localization, and a third relieves NALCN autoinhibition by displacing the C-terminal Interacting Helix, thereby activating Na⁺-leak current [PMID:35550517, PMID:32620897]. UNC80 also recruits Src family kinases to enable G-protein-independent activation of NALCN by neuropeptides such as substance P, and its C-terminal domain directs dendritic localization of the channel complex to regulate local membrane potential [PMID:19092807, PMID:19535918, PMID:32620897]. Loss-of-function mutations in human UNC80 cause a syndrome of hypotonia, severe intellectual disability, and dyskinesia, and Unc80-knockout mice are neonatal lethal [PMID:26545877, PMID:26708751, PMID:32620897].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of UNC-80 as a novel conserved neuronal protein required for proper axonal localization of NCA/NALCN channels established it as a channel-associated factor rather than a generic neuronal protein.\",\n      \"evidence\": \"C. elegans suppressor screen, genetic epistasis with synaptojanin, and immunolocalization of NCA-1/NCA-2\",\n      \"pmids\": [\"17825559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical interaction with NCA channels not yet demonstrated\", \"Mechanism of localization control unknown\", \"Mammalian relevance unconfirmed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that UNC-80 is required for substance P- and neurotensin-induced NALCN activation via a G-protein-independent, Src-kinase-dependent pathway established UNC80 as a signaling scaffold within the channel complex, not merely a trafficking factor.\",\n      \"evidence\": \"Electrophysiology in hippocampal and VTA neurons with pharmacological dissection of G-protein versus Src kinase pathways; C. elegans calcium imaging and localization\",\n      \"pmids\": [\"19092807\", \"18336069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between UNC80 and Src not yet shown\", \"Structural basis of scaffold function unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Biochemical evidence that UNC80 directly binds Src kinases and recruits them into the NALCN complex confirmed the scaffold model for G-protein-independent neuropeptide signaling.\",\n      \"evidence\": \"Co-immunoprecipitation and pulldown assays\",\n      \"pmids\": [\"19535918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP/pulldown from one lab without reciprocal validation in native tissue\", \"Binding domain on UNC80 not mapped\", \"Stoichiometry of Src within the complex unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that UNC80 bridges NALCN to UNC79 within the same complex and that this trimeric assembly is required for Ca²⁺-sensing-dependent Na⁺-leak current activation defined UNC80 as a central organizer coupling diverse extracellular signals to NALCN gating.\",\n      \"evidence\": \"Electrophysiology in cultured hippocampal neurons from nalcn and unc79 knockout mice with pharmacological G-protein manipulation\",\n      \"pmids\": [\"21040849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of UNC79–UNC80 interaction unknown\", \"How UNC80 couples to Ca²⁺-sensing GPCR signaling mechanistically unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reciprocal co-IP in Drosophila brain confirmed conserved complex formation and revealed that loss of UNC80 causes post-transcriptional degradation of all three subunits, indicating UNC80 stabilizes the complex beyond merely trafficking the channel.\",\n      \"evidence\": \"Immunoprecipitation from Drosophila brain, tissue-specific RNAi/rescue, western blotting\",\n      \"pmids\": [\"24223770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation pathway of unassembled subunits not identified\", \"Functional roles of UNC80 and UNC79 in circadian neurons beyond expression not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Human genetic studies linked UNC80 loss-of-function and missense mutations to a neurodevelopmental syndrome and directly demonstrated that patient-derived mutations abolish NALCN currents, confirming UNC80's essential role in human NALCN channel function.\",\n      \"evidence\": \"Whole-exome sequencing with Sanger validation (p.R51*); patch-clamp electrophysiology of p.Pro1700Ser in HEK293T cells\",\n      \"pmids\": [\"26545877\", \"26708751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No channel recordings from patient-derived neurons\", \"Genotype–phenotype correlation across mutation spectrum incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Domain-dissection studies revealed that UNC80's C-terminus mediates UNC79 interaction and contains a dendritic targeting signal separable from its channel-activating function, establishing that UNC80 independently regulates subcellular distribution of the NALCN complex.\",\n      \"evidence\": \"Co-IP, electrophysiology, live imaging in neurons, UNC80 knockout mice (neonatal lethal), domain deletion with patient mutations\",\n      \"pmids\": [\"32620897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of dendritic targeting signal not mapped to residues\", \"How dendritic versus somatic NALCN pools differentially affect excitability not quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The cryo-EM structure of the quaternary NALCN–FAM155A–UNC79–UNC80 complex resolved how UNC79–UNC80 form a piler-shaped heterodimer anchored to NALCN via three intracellular-loop contacts, two promoting surface expression and one relieving autoinhibition by displacing the CIH, providing a complete structural mechanism for UNC80-dependent channel activation.\",\n      \"evidence\": \"Cryo-EM structure determination with mutagenesis-based functional validation of localization and channel activity\",\n      \"pmids\": [\"35550517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational changes during channel gating not captured\", \"How Src kinase docks onto the structurally resolved complex remains unmodeled\", \"Structure determined in detergent — lipid bilayer context missing\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that Unc80 mRNA undergoes brain-specific ADAR2-dependent A-to-I RNA editing that modulates basal neuronal activity and glutamate levels in olfactory circuits introduced post-transcriptional regulation of UNC80 as a mechanism tuning channel complex function.\",\n      \"evidence\": \"CRISPR knock-in mouse models (gain- and loss-of-editing), neuronal activity measurements, glutamate quantification, behavioral assays\",\n      \"pmids\": [\"38892173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Edited residue's effect on UNC80 protein structure/function not determined\", \"Single lab study awaiting independent replication\", \"Whether editing alters NALCN current directly not tested electrophysiologically\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how Src kinase docks onto the structurally resolved NALCN–UNC80 complex, the identity of the dendritic targeting motif at residue-level resolution, and whether RNA editing of UNC80 directly modulates NALCN channel biophysics.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Src binding site on UNC80 not structurally mapped\", \"Dendritic targeting signal not mapped to specific residues\", \"Functional consequence of RNA editing on NALCN currents not tested electrophysiologically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 4, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 4, 8]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 4, 7, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"complexes\": [\"NALCN–FAM155A–UNC79–UNC80 channel complex\"],\n    \"partners\": [\"NALCN\", \"UNC79\", \"FAM155A\", \"SRC\"],\n    \"other_free_text\": []\n  }\n}\n```"}