{"gene":"AAAS","run_date":"2026-04-28T17:12:36","timeline":{"discoveries":[{"year":2001,"finding":"AAAS encodes a novel WD-repeat protein (ALADIN, 546 amino acids) whose loss-of-function mutations cause Triple A syndrome; RNA blotting showed marked expression in neuroendocrine and gastrointestinal structures predominantly affected in the disease, identifying AAAS as the causative gene.","method":"Positional cloning, mutation analysis in patients, RNA blotting","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — original disease-gene identification with multiple patient mutations and expression data, independently replicated","pmids":["11159947"],"is_preprint":false},{"year":2001,"finding":"AAAS mutations (including splice donor, nonsense, and missense variants) cause loss of function of the ALADIN protein and underlie Allgrove syndrome; mutations predicted to disrupt WD-repeat formation or beta-strand stability were identified, establishing structure-function relationships in ALADIN.","method":"Sequencing of AAAS gene, structural prediction of WD-repeat domains","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 3 — sequencing plus computational structural inference, single lab","pmids":["11701718"],"is_preprint":false},{"year":2008,"finding":"The ALADIN(L430F) missense mutation correctly localizes to nuclear pore complexes (NPCs) as shown by GFP-fusion transfection experiments, indicating this mutation impairs ALADIN function at the NPC without disrupting its localization.","method":"GFP-fusion transfection and fluorescence microscopy","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional inference, single lab","pmids":["18628786"],"is_preprint":false},{"year":2010,"finding":"Mutant ALADIN proteins can mislocalize to the cytoplasm and/or nucleus rather than the nuclear pore complex, resulting in impaired protein function; this mislocalization is a general mechanism by which AAAS mutations cause disease.","method":"Cellular localization studies of mutant ALADIN","journal":"Experimental and clinical endocrinology & diabetes","confidence":"Medium","confidence_rationale":"Tier 3 — localization data with functional consequence stated, moderate supporting evidence across labs","pmids":["20200814"],"is_preprint":false},{"year":2016,"finding":"The splice site mutation c.1331+1G>A in AAAS abolishes the exon 14 splice donor site and activates a cryptic intronic splice site, producing two aberrant transcripts (exon 14 skipping alone, and concurrent exon 14 skipping plus 99 bp intron 14 retention), both causing frameshifts with premature stop codons, demonstrating how a single splice mutation disrupts ALADIN protein structure.","method":"RT-PCR, sequencing, in silico splice site analysis","journal":"Hormone research in paediatrics","confidence":"Medium","confidence_rationale":"Tier 2 — direct transcript analysis with bioinformatic validation, single lab","pmids":["27414811"],"is_preprint":false},{"year":2020,"finding":"The C-terminal domain of ALADIN is essential for its correct targeting to the nuclear pore complex and protein function, as demonstrated by transcript analysis and expression studies of truncating variants affecting this region.","method":"Transcript analysis, expression studies in cells","journal":"Journal of endocrinological investigation","confidence":"Medium","confidence_rationale":"Tier 2 — functional characterization with transcript and expression data, single lab","pmids":["31939195"],"is_preprint":false},{"year":2022,"finding":"The novel ALADIN missense variant p.(Arg270Pro) demonstrates decreased localization to the nuclear pore complex in cells expressing the variant, functionally validating its pathogenicity in Triple A syndrome.","method":"Cellular localization assay (nuclear pore targeting) in patient-variant expressing cells","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence, single lab","pmids":["35570467"],"is_preprint":false}],"current_model":"ALADIN (encoded by AAAS) is a WD-repeat protein that localizes to the nuclear pore complex (NPC), where it is required for proper nuclear import/export; disease-causing mutations cause either mislocalization of ALADIN away from the NPC (to cytoplasm or nucleus) or, in some cases, retention at the NPC with impaired function, with the C-terminal domain critical for correct NPC targeting, collectively leading to the multisystem features of Triple A syndrome."},"narrative":{"teleology":[{"year":2001,"claim":"Positional cloning identified AAAS as the causative gene for Triple A syndrome, establishing that it encodes a novel WD-repeat protein (ALADIN) with predominant expression in the neuroendocrine and gastrointestinal tissues affected in the disease.","evidence":"Positional cloning, mutation screening of patient cohorts, and RNA blotting in human tissues","pmids":["11159947","11701718"],"confidence":"High","gaps":["Subcellular localization of ALADIN was not yet determined","The molecular function of ALADIN beyond its WD-repeat architecture was unknown","How loss of ALADIN leads to tissue-specific disease manifestations was unresolved"]},{"year":2008,"claim":"Demonstration that ALADIN localizes to the nuclear pore complex established it as a nucleoporin, and the finding that the L430F mutant retains NPC localization showed that mislocalization is not the only disease mechanism — some mutations impair function at the pore itself.","evidence":"GFP-fusion transfection and fluorescence microscopy in cultured cells","pmids":["18628786"],"confidence":"Medium","gaps":["The specific NPC-associated function disrupted by L430F was not identified","Which NPC subcomplex ALADIN associates with was not defined","No cargo molecules whose import or export depends on ALADIN were identified"]},{"year":2010,"claim":"Systematic localization studies of mutant ALADIN proteins showed that most pathogenic mutations cause mislocalization away from the NPC to the cytoplasm or nucleus, establishing mislocalization as the predominant disease mechanism.","evidence":"Cellular localization studies of multiple ALADIN mutants","pmids":["20200814"],"confidence":"Medium","gaps":["Whether mislocalized ALADIN retains any partial function was not tested","The structural basis for NPC targeting was not resolved","No quantitative nucleocytoplasmic transport assay was applied"]},{"year":2016,"claim":"Characterization of a splice-site mutation demonstrated that a single nucleotide change can produce multiple aberrant transcripts, each leading to frameshifts and premature termination, clarifying how non-coding mutations disrupt ALADIN protein integrity.","evidence":"RT-PCR, sequencing, and in silico splice site analysis of patient-derived RNA","pmids":["27414811"],"confidence":"Medium","gaps":["Whether truncated proteins are produced or degraded by NMD was not directly assessed","Functional consequences at the protein level were inferred, not measured"]},{"year":2020,"claim":"Transcript and expression studies of truncating variants pinpointed the C-terminal domain as essential for NPC targeting, providing the first domain-level requirement for ALADIN localization.","evidence":"Transcript analysis and expression studies in cells with truncating AAAS variants","pmids":["31939195"],"confidence":"Medium","gaps":["Minimal C-terminal sequence sufficient for NPC targeting was not defined","Direct binding partners mediating C-terminal-dependent NPC anchoring were not identified"]},{"year":2022,"claim":"Functional validation of the p.(Arg270Pro) variant demonstrated decreased NPC localization, extending the genotype–localization correlation to a novel pathogenic missense mutation within the WD-repeat domain.","evidence":"Cellular localization assay in cells expressing patient-derived ALADIN variant","pmids":["35570467"],"confidence":"Medium","gaps":["No high-resolution structural model of ALADIN at the NPC exists","How Arg270 contributes to WD-repeat folding or NPC binding was not mechanistically resolved"]},{"year":null,"claim":"The specific nucleocytoplasmic transport cargoes regulated by ALADIN and the molecular mechanism by which ALADIN loss leads to the tissue-specific pathology of Triple A syndrome remain unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No transport cargo dependent on ALADIN has been identified in the primary literature","The NPC subcomplex to which ALADIN is anchored has not been defined","How ALADIN dysfunction selectively damages adrenal, esophageal, and lacrimal tissues is unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2,3,5,6]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,3,5]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"ALADIN, encoded by AAAS, is a 546-amino-acid WD-repeat nucleoporin that localizes to the nuclear pore complex (NPC), where it participates in nucleocytoplasmic transport [PMID:11159947, PMID:18628786]. The C-terminal domain of ALADIN is essential for its correct targeting to the NPC; most disease-causing mutations mislocalize the protein to the cytoplasm or nucleus, abolishing function, although certain missense mutations (e.g., L430F) retain NPC localization but impair function at the pore [PMID:31939195, PMID:18628786, PMID:20200814]. Loss-of-function mutations in AAAS cause Triple A (Allgrove) syndrome, a multisystem disorder characterized by adrenal insufficiency, achalasia, and alacrima, consistent with the gene's predominant expression in neuroendocrine and gastrointestinal tissues [PMID:11159947, PMID:11701718]."},"prefetch_data":{"uniprot":{"accession":"Q9NRG9","full_name":"Aladin","aliases":["Adracalin"],"length_aa":546,"mass_kda":59.6,"function":"Plays a role in the normal development of the peripheral and central nervous system (PubMed:11062474, PubMed:11159947, PubMed:16022285). Required for the correct localization of aurora kinase AURKA and the microtubule minus end-binding protein NUMA1 as well as a subset of AURKA targets which ensures proper spindle formation and timely chromosome alignment (PubMed:26246606)","subcellular_location":"Nucleus, nuclear pore complex; Cytoplasm, cytoskeleton, spindle pole; Nucleus envelope","url":"https://www.uniprot.org/uniprotkb/Q9NRG9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AAAS","classification":"Not Classified","n_dependent_lines":217,"n_total_lines":1208,"dependency_fraction":0.17963576158940397},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AAAS","total_profiled":1310},"omim":[{"mim_id":"615510","title":"ALACRIMA, ACHALASIA, AND IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME; AAMR","url":"https://www.omim.org/entry/615510"},{"mim_id":"615495","title":"GDP-MANNOSE PYROPHOSPHORYLASE A; GMPPA","url":"https://www.omim.org/entry/615495"},{"mim_id":"615356","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 18; LGMDR18","url":"https://www.omim.org/entry/615356"},{"mim_id":"613220","title":"TRANSMEMBRANE PROTEIN 18; TMEM18","url":"https://www.omim.org/entry/613220"},{"mim_id":"612016","title":"COENZYME Q10 DEFICIENCY, PRIMARY, 4; COQ10D4","url":"https://www.omim.org/entry/612016"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","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/AAAS"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NRG9","domains":[{"cath_id":"-","chopping":"2-43_387-492","consensus_level":"medium","plddt":80.3601,"start":2,"end":492},{"cath_id":"-","chopping":"77-134","consensus_level":"medium","plddt":70.9838,"start":77,"end":134}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRG9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRG9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRG9-F1-predicted_aligned_error_v6.png","plddt_mean":75.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AAAS","jax_strain_url":"https://www.jax.org/strain/search?query=AAAS"},"sequence":{"accession":"Q9NRG9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRG9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRG9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRG9"}},"corpus_meta":[{"pmid":"26044582","id":"PMC_26044582","title":"Inflammatory 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RNA blotting showed marked expression in neuroendocrine and gastrointestinal structures predominantly affected in the disease, identifying AAAS as the causative gene.\",\n      \"method\": \"Positional cloning, mutation analysis in patients, RNA blotting\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original disease-gene identification with multiple patient mutations and expression data, independently replicated\",\n      \"pmids\": [\"11159947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"AAAS mutations (including splice donor, nonsense, and missense variants) cause loss of function of the ALADIN protein and underlie Allgrove syndrome; mutations predicted to disrupt WD-repeat formation or beta-strand stability were identified, establishing structure-function relationships in ALADIN.\",\n      \"method\": \"Sequencing of AAAS gene, structural prediction of WD-repeat domains\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — sequencing plus computational structural inference, single lab\",\n      \"pmids\": [\"11701718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The ALADIN(L430F) missense mutation correctly localizes to nuclear pore complexes (NPCs) as shown by GFP-fusion transfection experiments, indicating this mutation impairs ALADIN function at the NPC without disrupting its localization.\",\n      \"method\": \"GFP-fusion transfection and fluorescence microscopy\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional inference, single lab\",\n      \"pmids\": [\"18628786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mutant ALADIN proteins can mislocalize to the cytoplasm and/or nucleus rather than the nuclear pore complex, resulting in impaired protein function; this mislocalization is a general mechanism by which AAAS mutations cause disease.\",\n      \"method\": \"Cellular localization studies of mutant ALADIN\",\n      \"journal\": \"Experimental and clinical endocrinology & diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization data with functional consequence stated, moderate supporting evidence across labs\",\n      \"pmids\": [\"20200814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The splice site mutation c.1331+1G>A in AAAS abolishes the exon 14 splice donor site and activates a cryptic intronic splice site, producing two aberrant transcripts (exon 14 skipping alone, and concurrent exon 14 skipping plus 99 bp intron 14 retention), both causing frameshifts with premature stop codons, demonstrating how a single splice mutation disrupts ALADIN protein structure.\",\n      \"method\": \"RT-PCR, sequencing, in silico splice site analysis\",\n      \"journal\": \"Hormone research in paediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcript analysis with bioinformatic validation, single lab\",\n      \"pmids\": [\"27414811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The C-terminal domain of ALADIN is essential for its correct targeting to the nuclear pore complex and protein function, as demonstrated by transcript analysis and expression studies of truncating variants affecting this region.\",\n      \"method\": \"Transcript analysis, expression studies in cells\",\n      \"journal\": \"Journal of endocrinological investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization with transcript and expression data, single lab\",\n      \"pmids\": [\"31939195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The novel ALADIN missense variant p.(Arg270Pro) demonstrates decreased localization to the nuclear pore complex in cells expressing the variant, functionally validating its pathogenicity in Triple A syndrome.\",\n      \"method\": \"Cellular localization assay (nuclear pore targeting) in patient-variant expressing cells\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence, single lab\",\n      \"pmids\": [\"35570467\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALADIN (encoded by AAAS) is a WD-repeat protein that localizes to the nuclear pore complex (NPC), where it is required for proper nuclear import/export; disease-causing mutations cause either mislocalization of ALADIN away from the NPC (to cytoplasm or nucleus) or, in some cases, retention at the NPC with impaired function, with the C-terminal domain critical for correct NPC targeting, collectively leading to the multisystem features of Triple A syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ALADIN, encoded by AAAS, is a 546-amino-acid WD-repeat nucleoporin that localizes to the nuclear pore complex (NPC), where it participates in nucleocytoplasmic transport [PMID:11159947, PMID:18628786]. The C-terminal domain of ALADIN is essential for its correct targeting to the NPC; most disease-causing mutations mislocalize the protein to the cytoplasm or nucleus, abolishing function, although certain missense mutations (e.g., L430F) retain NPC localization but impair function at the pore [PMID:31939195, PMID:18628786, PMID:20200814]. Loss-of-function mutations in AAAS cause Triple A (Allgrove) syndrome, a multisystem disorder characterized by adrenal insufficiency, achalasia, and alacrima, consistent with the gene's predominant expression in neuroendocrine and gastrointestinal tissues [PMID:11159947, PMID:11701718].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Positional cloning identified AAAS as the causative gene for Triple A syndrome, establishing that it encodes a novel WD-repeat protein (ALADIN) with predominant expression in the neuroendocrine and gastrointestinal tissues affected in the disease.\",\n      \"evidence\": \"Positional cloning, mutation screening of patient cohorts, and RNA blotting in human tissues\",\n      \"pmids\": [\"11159947\", \"11701718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Subcellular localization of ALADIN was not yet determined\",\n        \"The molecular function of ALADIN beyond its WD-repeat architecture was unknown\",\n        \"How loss of ALADIN leads to tissue-specific disease manifestations was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that ALADIN localizes to the nuclear pore complex established it as a nucleoporin, and the finding that the L430F mutant retains NPC localization showed that mislocalization is not the only disease mechanism — some mutations impair function at the pore itself.\",\n      \"evidence\": \"GFP-fusion transfection and fluorescence microscopy in cultured cells\",\n      \"pmids\": [\"18628786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific NPC-associated function disrupted by L430F was not identified\",\n        \"Which NPC subcomplex ALADIN associates with was not defined\",\n        \"No cargo molecules whose import or export depends on ALADIN were identified\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Systematic localization studies of mutant ALADIN proteins showed that most pathogenic mutations cause mislocalization away from the NPC to the cytoplasm or nucleus, establishing mislocalization as the predominant disease mechanism.\",\n      \"evidence\": \"Cellular localization studies of multiple ALADIN mutants\",\n      \"pmids\": [\"20200814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether mislocalized ALADIN retains any partial function was not tested\",\n        \"The structural basis for NPC targeting was not resolved\",\n        \"No quantitative nucleocytoplasmic transport assay was applied\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Characterization of a splice-site mutation demonstrated that a single nucleotide change can produce multiple aberrant transcripts, each leading to frameshifts and premature termination, clarifying how non-coding mutations disrupt ALADIN protein integrity.\",\n      \"evidence\": \"RT-PCR, sequencing, and in silico splice site analysis of patient-derived RNA\",\n      \"pmids\": [\"27414811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether truncated proteins are produced or degraded by NMD was not directly assessed\",\n        \"Functional consequences at the protein level were inferred, not measured\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Transcript and expression studies of truncating variants pinpointed the C-terminal domain as essential for NPC targeting, providing the first domain-level requirement for ALADIN localization.\",\n      \"evidence\": \"Transcript analysis and expression studies in cells with truncating AAAS variants\",\n      \"pmids\": [\"31939195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Minimal C-terminal sequence sufficient for NPC targeting was not defined\",\n        \"Direct binding partners mediating C-terminal-dependent NPC anchoring were not identified\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Functional validation of the p.(Arg270Pro) variant demonstrated decreased NPC localization, extending the genotype–localization correlation to a novel pathogenic missense mutation within the WD-repeat domain.\",\n      \"evidence\": \"Cellular localization assay in cells expressing patient-derived ALADIN variant\",\n      \"pmids\": [\"35570467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structural model of ALADIN at the NPC exists\",\n        \"How Arg270 contributes to WD-repeat folding or NPC binding was not mechanistically resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific nucleocytoplasmic transport cargoes regulated by ALADIN and the molecular mechanism by which ALADIN loss leads to the tissue-specific pathology of Triple A syndrome remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No transport cargo dependent on ALADIN has been identified in the primary literature\",\n        \"The NPC subcomplex to which ALADIN is anchored has not been defined\",\n        \"How ALADIN dysfunction selectively damages adrenal, esophageal, and lacrimal tissues is unexplained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2, 3, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 3, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}