{"gene":"LNPK","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2018,"finding":"Loss-of-function mutations in LNPK (encoding lunapark) cause aberrant ER structures and increased luminal mass density in affected cells, consistent with lunapark's proposed role as a curvature-stabilizing protein within tubular three-way junctions of the endoplasmic reticulum. LNPK is expressed during brain development and is present in neurite-like processes in differentiating human neural progenitor cells.","method":"Patient-derived cell analysis (absence of full-length lunapark protein confirmed), ER morphology assessment, expression analysis in human/mouse brain development, immunostaining in differentiating neural progenitor cells","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function patient cells with defined cellular phenotype (aberrant ER structures), two orthogonal methods (protein analysis + ER morphology), single lab","pmids":["30032983"],"is_preprint":false},{"year":2025,"finding":"Compound heterozygous splice site mutations in LNPK lead to exon skipping (not intron retention), activating the nonsense-mediated decay (NMD) pathway, which causes severe reduction in LNPK transcript and loss of lunapark protein. Treatment with an NMD inhibitor increases LNPK transcript in affected cells, indicating NMD-mediated degradation as the primary mechanism of loss of function. Additionally, LNPK is subject to genetic compensation, as both the affected individual's and her mother's cells show increased transcript upon NMD inhibition.","method":"Cultured patient fibroblasts; RT-PCR/RNA analysis for exon skipping; NMD inhibitor treatment; protein expression analysis by western blot","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular analysis of patient fibroblasts with NMD inhibitor rescue, two orthogonal methods (RNA and protein), single lab","pmids":["41204669"],"is_preprint":false},{"year":2025,"finding":"Compound heterozygous splice site mutations in LNPK cause exon skipping leading to NMD-mediated transcript degradation and severe loss of lunapark protein; LNPK undergoes genetic compensation as evidenced by elevated transcript levels upon NMD inhibition in affected and carrier cells.","method":"Cultured patient fibroblasts; RNA analysis for exon skipping and NMD; NMD inhibitor treatment; protein expression analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, overlapping findings with peer-reviewed PMID 41204669, single lab, single study","pmids":["bio_10.1101_2025.05.30.656906"],"is_preprint":true}],"current_model":"LNPK encodes lunapark, an endoplasmic reticulum-associated protein that stabilizes curvature at tubular three-way junctions of the ER; loss-of-function mutations cause aberrant ER structure, and pathogenic splice site variants result in exon skipping and NMD-mediated transcript degradation, leading to absence of lunapark protein and a recessive neurodevelopmental syndrome characterized by intellectual disability, epilepsy, and corpus callosum hypoplasia."},"narrative":{"mechanistic_narrative":"LNPK encodes lunapark, an endoplasmic reticulum-associated protein that stabilizes membrane curvature at the tubular three-way junctions of the ER; loss of full-length lunapark produces aberrant ER structures with increased luminal mass density [PMID:30032983]. LNPK is expressed during brain development and localizes to neurite-like processes in differentiating human neural progenitor cells, linking ER architecture to neurodevelopment [PMID:30032983]. Biallelic loss-of-function mutations in LNPK cause a recessive neurodevelopmental syndrome; pathogenic compound heterozygous splice site variants trigger exon skipping that activates nonsense-mediated decay, severely reducing LNPK transcript and abolishing lunapark protein, with NMD inhibitor treatment restoring transcript levels in patient and carrier cells [PMID:30032983, PMID:41204669]. Beyond its curvature-stabilizing role at ER junctions, the molecular partners and biochemical activity of lunapark have not been characterized in the available corpus.","teleology":[{"year":2018,"claim":"Established that LNPK loss of function disrupts ER morphology and tied the gene to brain development, defining lunapark as a curvature-stabilizing ER protein with neurodevelopmental relevance.","evidence":"Patient-derived cell analysis confirming absence of full-length lunapark, ER morphology assessment, and expression/immunostaining in human neural progenitor cells","pmids":["30032983"],"confidence":"Medium","gaps":["Direct biochemical demonstration of curvature stabilization not shown","No physical interaction partners at three-way junctions identified","Causal link between ER defect and neuronal phenotype not mechanistically resolved"]},{"year":2025,"claim":"Resolved the molecular mechanism of LNPK loss by showing splice variants cause exon skipping and NMD-mediated transcript degradation rather than intron retention, with NMD inhibition rescuing transcript levels.","evidence":"Patient fibroblasts analyzed by RT-PCR/RNA analysis for exon skipping, NMD inhibitor treatment, and western blot for protein loss","pmids":["41204669"],"confidence":"Medium","gaps":["Genetic compensation observed but its mechanism not defined","Single-lab analysis of a single family","Functional consequence of restored transcript on ER structure not tested"]},{"year":null,"claim":"The biochemical activity of lunapark, its direct binding partners at ER three-way junctions, and the causal chain from ER structural defect to the neurodevelopmental phenotype remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic or binding activity assigned","No interactome data in the corpus","No animal or neuronal model linking ER defect to circuit-level phenotype"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C0E8","full_name":"Endoplasmic reticulum junction formation protein lunapark","aliases":["ER junction formation factor lunapark"],"length_aa":428,"mass_kda":47.7,"function":"Endoplasmic reticulum (ER)-shaping membrane protein that plays a role in determining ER morphology (PubMed:30032983). Involved in the stabilization of nascent three-way ER tubular junctions within the ER network (PubMed:24223779, PubMed:25404289, PubMed:25548161, PubMed:27619977). May also play a role as a curvature-stabilizing protein within the three-way ER tubular junction network (PubMed:25404289). May be involved in limb development (By similarity). Is involved in central nervous system development (PubMed:30032983)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9C0E8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LNPK","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000144320","cell_line_id":"CID000839","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"LNP","stoichiometry":10.0},{"gene":"FOXG1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000839","total_profiled":1310},"omim":[{"mim_id":"618090","title":"NEURODEVELOPMENTAL DISORDER WITH EPILEPSY AND HYPOPLASIA OF THE CORPUS CALLOSUM; NEDEHCC","url":"https://www.omim.org/entry/618090"},{"mim_id":"610236","title":"LUNAPARK; LNPK","url":"https://www.omim.org/entry/610236"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LNPK"},"hgnc":{"alias_symbol":["Ul","LNP1","LNP"],"prev_symbol":["KIAA1715"]},"alphafold":{"accession":"Q9C0E8","domains":[{"cath_id":"-","chopping":"13-148","consensus_level":"high","plddt":89.9824,"start":13,"end":148},{"cath_id":"-","chopping":"254-304","consensus_level":"high","plddt":88.5861,"start":254,"end":304}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0E8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0E8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0E8-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LNPK","jax_strain_url":"https://www.jax.org/strain/search?query=LNPK"},"sequence":{"accession":"Q9C0E8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C0E8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C0E8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0E8"}},"corpus_meta":[{"pmid":"8139009","id":"PMC_8139009","title":"A novel latency-active promoter is contained within the herpes simplex virus type 1 UL flanking repeats.","date":"1994","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8139009","citation_count":155,"is_preprint":false},{"pmid":"9342042","id":"PMC_9342042","title":"Ulnaless (Ul), a regulatory mutation inducing both loss-of-function and gain-of-function of posterior Hoxd genes.","date":"1997","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9342042","citation_count":98,"is_preprint":false},{"pmid":"8222132","id":"PMC_8222132","title":"Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS 49). 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The Journal of the Pakistan Medical Association","url":"https://pubmed.ncbi.nlm.nih.gov/7623407","citation_count":0,"is_preprint":false},{"pmid":"8841546","id":"PMC_8841546","title":"Synthesis and NMR applications of isotopically labeled 2'-deoxynucleosides. Stereospecific deuteration of the C2' methylene in [ul-11 C/15N]deoxyadenosine.","date":"1995","source":"Nucleic acids symposium series","url":"https://pubmed.ncbi.nlm.nih.gov/8841546","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.30.656906","title":"Exon-skipping and genetic compensation due to biallelic mutations in the neurodevelopmental disease gene  <i>LNPK</i>","date":"2025-06-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.30.656906","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32413,"output_tokens":910,"usd":0.055445,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7405,"output_tokens":1190,"usd":0.033388,"stage2_stop_reason":"end_turn"},"total_usd":0.088833,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function mutations in LNPK (encoding lunapark) cause aberrant ER structures and increased luminal mass density in affected cells, consistent with lunapark's proposed role as a curvature-stabilizing protein within tubular three-way junctions of the endoplasmic reticulum. LNPK is expressed during brain development and is present in neurite-like processes in differentiating human neural progenitor cells.\",\n      \"method\": \"Patient-derived cell analysis (absence of full-length lunapark protein confirmed), ER morphology assessment, expression analysis in human/mouse brain development, immunostaining in differentiating neural progenitor cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function patient cells with defined cellular phenotype (aberrant ER structures), two orthogonal methods (protein analysis + ER morphology), single lab\",\n      \"pmids\": [\"30032983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compound heterozygous splice site mutations in LNPK lead to exon skipping (not intron retention), activating the nonsense-mediated decay (NMD) pathway, which causes severe reduction in LNPK transcript and loss of lunapark protein. Treatment with an NMD inhibitor increases LNPK transcript in affected cells, indicating NMD-mediated degradation as the primary mechanism of loss of function. Additionally, LNPK is subject to genetic compensation, as both the affected individual's and her mother's cells show increased transcript upon NMD inhibition.\",\n      \"method\": \"Cultured patient fibroblasts; RT-PCR/RNA analysis for exon skipping; NMD inhibitor treatment; protein expression analysis by western blot\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular analysis of patient fibroblasts with NMD inhibitor rescue, two orthogonal methods (RNA and protein), single lab\",\n      \"pmids\": [\"41204669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compound heterozygous splice site mutations in LNPK cause exon skipping leading to NMD-mediated transcript degradation and severe loss of lunapark protein; LNPK undergoes genetic compensation as evidenced by elevated transcript levels upon NMD inhibition in affected and carrier cells.\",\n      \"method\": \"Cultured patient fibroblasts; RNA analysis for exon skipping and NMD; NMD inhibitor treatment; protein expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, overlapping findings with peer-reviewed PMID 41204669, single lab, single study\",\n      \"pmids\": [\"bio_10.1101_2025.05.30.656906\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LNPK encodes lunapark, an endoplasmic reticulum-associated protein that stabilizes curvature at tubular three-way junctions of the ER; loss-of-function mutations cause aberrant ER structure, and pathogenic splice site variants result in exon skipping and NMD-mediated transcript degradation, leading to absence of lunapark protein and a recessive neurodevelopmental syndrome characterized by intellectual disability, epilepsy, and corpus callosum hypoplasia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LNPK encodes lunapark, an endoplasmic reticulum-associated protein that stabilizes membrane curvature at the tubular three-way junctions of the ER; loss of full-length lunapark produces aberrant ER structures with increased luminal mass density [#0]. LNPK is expressed during brain development and localizes to neurite-like processes in differentiating human neural progenitor cells, linking ER architecture to neurodevelopment [#0]. Biallelic loss-of-function mutations in LNPK cause a recessive neurodevelopmental syndrome; pathogenic compound heterozygous splice site variants trigger exon skipping that activates nonsense-mediated decay, severely reducing LNPK transcript and abolishing lunapark protein, with NMD inhibitor treatment restoring transcript levels in patient and carrier cells [#0, #1]. Beyond its curvature-stabilizing role at ER junctions, the molecular partners and biochemical activity of lunapark have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that LNPK loss of function disrupts ER morphology and tied the gene to brain development, defining lunapark as a curvature-stabilizing ER protein with neurodevelopmental relevance.\",\n      \"evidence\": \"Patient-derived cell analysis confirming absence of full-length lunapark, ER morphology assessment, and expression/immunostaining in human neural progenitor cells\",\n      \"pmids\": [\"30032983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical demonstration of curvature stabilization not shown\",\n        \"No physical interaction partners at three-way junctions identified\",\n        \"Causal link between ER defect and neuronal phenotype not mechanistically resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the molecular mechanism of LNPK loss by showing splice variants cause exon skipping and NMD-mediated transcript degradation rather than intron retention, with NMD inhibition rescuing transcript levels.\",\n      \"evidence\": \"Patient fibroblasts analyzed by RT-PCR/RNA analysis for exon skipping, NMD inhibitor treatment, and western blot for protein loss\",\n      \"pmids\": [\"41204669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genetic compensation observed but its mechanism not defined\",\n        \"Single-lab analysis of a single family\",\n        \"Functional consequence of restored transcript on ER structure not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of lunapark, its direct binding partners at ER three-way junctions, and the causal chain from ER structural defect to the neurodevelopmental phenotype remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No enzymatic or binding activity assigned\",\n        \"No interactome data in the corpus\",\n        \"No animal or neuronal model linking ER defect to circuit-level phenotype\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}