{"gene":"SPG21","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2003,"finding":"SPG21 encodes maspardin (ACP33), and a single base-pair insertion (601insA) causing premature truncation (fs201-212X213) underlies Mast syndrome (autosomal recessive hereditary spastic paraplegia with dementia), mapping the SPG21 locus to chromosome 15q22.31. The encoded protein was shown to localize to intracellular endosomal/trans-Golgi transportation vesicles, suggesting a role in protein transport and sorting.","method":"Genetic mapping in an Amish pedigree, sequence analysis of candidate genes, identification of homozygous frameshift mutation in all 14 affected cases; protein localization noted from prior studies","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic mapping with mutation identification in a large pedigree, replicated across 14 affected individuals; foundational disease-gene paper","pmids":["14564668"],"is_preprint":false},{"year":2000,"finding":"ACP33 (maspardin/SPG21 protein) was identified as a novel intracellular binding partner of CD4 via a yeast two-hybrid screen. The interaction is mediated by the noncatalytic alpha/beta hydrolase fold domain of ACP33, and depends on two conserved hydrophobic amino acids at the CD4 carboxyl terminus. Deletion of these CD4 residues abolished ACP33 binding and enhanced CD4-mediated T cell costimulation, suggesting ACP33 modulates the stimulatory activity of CD4.","method":"Yeast two-hybrid screen, co-immunoprecipitation, domain mapping by deletion mutagenesis, functional T cell activation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid with functional validation and domain mapping, single lab","pmids":["11113139"],"is_preprint":false},{"year":2009,"finding":"Maspardin (SPG21 protein) localizes prominently to cytoplasm and to membranes consistent with trans-Golgi network/late endosomal compartments. Immunoprecipitation of maspardin followed by mass spectrometry identified the aldehyde dehydrogenase ALDH16A1 as a binding partner, confirmed by co-immunoprecipitation of overexpressed proteins and fusion protein pull-down experiments, with colocalization of the two proteins in cells.","method":"Immunofluorescence localization, co-immunoprecipitation with mass spectrometry identification, fusion protein pull-down, colocalization by confocal microscopy","journal":"Neurogenetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — subcellular localization by imaging plus reciprocal co-IP/pulldown with MS identification, single lab, moderate methods","pmids":["19184135"],"is_preprint":false}],"current_model":"Maspardin (SPG21/ACP33) is a ~33 kDa protein that localizes to the cytoplasm and trans-Golgi network/late endosomal compartments; it functions in protein transport and sorting, interacts with CD4 via its alpha/beta hydrolase fold domain to modulate T cell signaling, and interacts with the aldehyde dehydrogenase ALDH16A1, with loss-of-function frameshift mutations causing Mast syndrome (autosomal recessive hereditary spastic paraplegia with dementia)."},"narrative":{"teleology":[{"year":2000,"claim":"The first molecular function attributed to maspardin was as an intracellular negative regulator of CD4 signaling, establishing that its alpha/beta hydrolase fold domain mediates a direct protein–protein interaction rather than catalysis.","evidence":"Yeast two-hybrid screen, co-immunoprecipitation, deletion mutagenesis, and T cell activation assays in vitro","pmids":["11113139"],"confidence":"Medium","gaps":["Interaction identified in a single lab without independent replication","Endogenous complex stoichiometry and physiological relevance in primary T cells not established","Whether the hydrolase fold retains any residual catalytic activity remains untested"]},{"year":2003,"claim":"Genetic mapping of Mast syndrome to SPG21 established maspardin as essential for neuronal maintenance and linked its loss to hereditary spastic paraplegia with dementia, placing the protein's transport/sorting function in a disease context.","evidence":"Positional cloning in an Amish pedigree with homozygous frameshift mutation (601insA) confirmed across 14 affected individuals","pmids":["14564668"],"confidence":"High","gaps":["Molecular mechanism by which loss of maspardin leads to corticospinal tract degeneration is unknown","No rescue experiment or animal model reported in this study","Specific cargo sorted by maspardin-containing vesicles not identified"]},{"year":2009,"claim":"Identification of ALDH16A1 as a maspardin binding partner expanded the protein's interactome beyond CD4 and suggested a functional connection between endosomal/Golgi trafficking and aldehyde metabolism.","evidence":"Immunoprecipitation followed by mass spectrometry, reciprocal co-IP of overexpressed proteins, fusion protein pull-down, and confocal colocalization","pmids":["19184135"],"confidence":"Medium","gaps":["Functional consequence of the maspardin–ALDH16A1 interaction is unknown","Interaction validated only with overexpressed or tagged proteins; endogenous validation at physiological levels lacking","Whether ALDH16A1 binding is relevant to the Mast syndrome phenotype is untested"]},{"year":null,"claim":"The precise cargo(s) sorted by maspardin in endosomal/trans-Golgi trafficking, the structural basis of its protein interactions, and the cellular pathway connecting maspardin loss to neurodegeneration remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No animal or neuronal model characterizing maspardin loss-of-function phenotypes at the cellular level","No structural model of maspardin or its complexes","Relationship between the CD4 and ALDH16A1 interactions and neuronal function is unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CD4","ALDH16A1"],"other_free_text":[]},"mechanistic_narrative":"Maspardin (SPG21/ACP33) is a cytoplasmic and trans-Golgi network/late endosomal protein that functions in intracellular protein transport and sorting [PMID:14564668, PMID:19184135]. It contains a noncatalytic alpha/beta hydrolase fold domain that mediates direct interaction with the cytoplasmic tail of CD4, negatively modulating CD4-dependent T cell costimulation [PMID:11113139]. Maspardin also binds the aldehyde dehydrogenase ALDH16A1, with which it colocalizes in endosomal/Golgi compartments [PMID:19184135]. A homozygous frameshift mutation in SPG21 (601insA) causes Mast syndrome, an autosomal recessive hereditary spastic paraplegia with dementia [PMID:14564668]."},"prefetch_data":{"uniprot":{"accession":"Q9NZD8","full_name":"Maspardin","aliases":["Acid cluster protein 33","Spastic paraplegia 21 autosomal recessive Mast syndrome protein","Spastic paraplegia 21 protein"],"length_aa":308,"mass_kda":35.0,"function":"May play a role as a negative regulatory factor in CD4-dependent T-cell activation","subcellular_location":"Cytoplasm, cytosol; Membrane; Endosome membrane; Golgi apparatus, trans-Golgi network membrane","url":"https://www.uniprot.org/uniprotkb/Q9NZD8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPG21","classification":"Not 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AUTOSOMAL RECESSIVE; SPG5A","url":"https://www.omim.org/entry/270800"},{"mim_id":"248900","title":"MAST SYNDROME; MASTS","url":"https://www.omim.org/entry/248900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPG21"},"hgnc":{"alias_symbol":["ACP33","GL010","BM-019","MAST","ABHD21"],"prev_symbol":[]},"alphafold":{"accession":"Q9NZD8","domains":[{"cath_id":"3.40.50.1820","chopping":"3-306","consensus_level":"high","plddt":93.3592,"start":3,"end":306}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZD8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZD8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZD8-F1-predicted_aligned_error_v6.png","plddt_mean":92.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPG21","jax_strain_url":"https://www.jax.org/strain/search?query=SPG21"},"sequence":{"accession":"Q9NZD8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZD8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZD8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZD8"}},"corpus_meta":[{"pmid":"9354811","id":"PMC_9354811","title":"Mast 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Interaction with CD4 is abolished by deletion of two conserved hydrophobic amino acids from the CD4 carboxyl terminus, and ACP33 binding is proposed to modulate the stimulatory activity of CD4 in T cell activation.\",\n      \"method\": \"Yeast two-hybrid screen with intracellular portion of CD4, confirmed by co-immunoprecipitation and functional T cell activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed by two-hybrid + co-IP + mutagenesis, single lab\",\n      \"pmids\": [\"11113139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Maspardin (ACP33/SPG21 protein) localizes prominently to cytoplasm and to membranes consistent with trans-Golgi network/late endosomal compartments. It was found to interact with the aldehyde dehydrogenase ALDH16A1, as identified by immunoprecipitation followed by mass spectrometry, confirmed by overexpressed protein co-immunoprecipitation, fusion protein pull-down, and colocalization in cells.\",\n      \"method\": \"Immunoprecipitation with mass spectrometry identification of coprecipitating proteins, confirmed by overexpressed protein co-IP and fusion protein pull-down; subcellular localization by immunofluorescence\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by multiple orthogonal methods (MS, co-IP, pull-down, colocalization) in single lab\",\n      \"pmids\": [\"19184135\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Maspardin (ACP33), the SPG21 protein, localizes to the cytoplasm and trans-Golgi network/late endosomal compartments, where it interacts with ALDH16A1 via its alpha/beta hydrolase fold domain; this same domain mediates binding to the cytoplasmic tail of CD4, suggesting maspardin functions as a protein-protein interaction scaffold at endosomal membranes, with loss of function causing the Mast syndrome form of hereditary spastic paraplegia.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"SPG21 encodes maspardin (ACP33), and a single base-pair insertion (601insA) causing premature truncation (fs201-212X213) underlies Mast syndrome (autosomal recessive hereditary spastic paraplegia with dementia), mapping the SPG21 locus to chromosome 15q22.31. The encoded protein was shown to localize to intracellular endosomal/trans-Golgi transportation vesicles, suggesting a role in protein transport and sorting.\",\n      \"method\": \"Genetic mapping in an Amish pedigree, sequence analysis of candidate genes, identification of homozygous frameshift mutation in all 14 affected cases; protein localization noted from prior studies\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mapping with mutation identification in a large pedigree, replicated across 14 affected individuals; foundational disease-gene paper\",\n      \"pmids\": [\"14564668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ACP33 (maspardin/SPG21 protein) was identified as a novel intracellular binding partner of CD4 via a yeast two-hybrid screen. The interaction is mediated by the noncatalytic alpha/beta hydrolase fold domain of ACP33, and depends on two conserved hydrophobic amino acids at the CD4 carboxyl terminus. Deletion of these CD4 residues abolished ACP33 binding and enhanced CD4-mediated T cell costimulation, suggesting ACP33 modulates the stimulatory activity of CD4.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, domain mapping by deletion mutagenesis, functional T cell activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid with functional validation and domain mapping, single lab\",\n      \"pmids\": [\"11113139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Maspardin (SPG21 protein) localizes prominently to cytoplasm and to membranes consistent with trans-Golgi network/late endosomal compartments. Immunoprecipitation of maspardin followed by mass spectrometry identified the aldehyde dehydrogenase ALDH16A1 as a binding partner, confirmed by co-immunoprecipitation of overexpressed proteins and fusion protein pull-down experiments, with colocalization of the two proteins in cells.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation with mass spectrometry identification, fusion protein pull-down, colocalization by confocal microscopy\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — subcellular localization by imaging plus reciprocal co-IP/pulldown with MS identification, single lab, moderate methods\",\n      \"pmids\": [\"19184135\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Maspardin (SPG21/ACP33) is a ~33 kDa protein that localizes to the cytoplasm and trans-Golgi network/late endosomal compartments; it functions in protein transport and sorting, interacts with CD4 via its alpha/beta hydrolase fold domain to modulate T cell signaling, and interacts with the aldehyde dehydrogenase ALDH16A1, with loss-of-function frameshift mutations causing Mast syndrome (autosomal recessive hereditary spastic paraplegia with dementia).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SPG21 encodes maspardin (ACP33), an intracellular protein that harbors a noncatalytic alpha/beta hydrolase fold domain functioning as a protein–protein interaction scaffold. Maspardin localizes to the cytoplasm and trans-Golgi network/late endosomal compartment membranes, where it binds ALDH16A1 [PMID:19184135] and the cytoplasmic tail of CD4 via conserved hydrophobic residues [PMID:11113139]. Loss-of-function mutations in SPG21 cause Mast syndrome, a form of hereditary spastic paraplegia.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying maspardin as a CD4-binding protein established that its alpha/beta hydrolase fold domain mediates protein–protein interactions rather than catalytic activity, linking it to T cell signaling.\",\n      \"evidence\": \"Yeast two-hybrid screen with the CD4 intracellular domain, confirmed by co-immunoprecipitation and mutagenesis in T cell activation assays\",\n      \"pmids\": [\"11113139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction demonstrated primarily by overexpression-based methods in a single lab; independent confirmation lacking\",\n        \"Physiological relevance of the CD4–maspardin interaction in T cells in vivo is unresolved\",\n        \"Whether the hydrolase fold has any residual enzymatic activity remains untested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that maspardin resides at trans-Golgi/late endosomal membranes and physically associates with ALDH16A1 placed its scaffolding function in a specific endomembrane trafficking context relevant to neuronal biology.\",\n      \"evidence\": \"Immunoprecipitation–mass spectrometry identification of ALDH16A1, confirmed by co-IP, pull-down, and colocalization; immunofluorescence localization\",\n      \"pmids\": [\"19184135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the maspardin–ALDH16A1 interaction is unknown\",\n        \"No demonstration of how maspardin loss perturbs endosomal/TGN trafficking\",\n        \"No animal or neuronal model confirming these interactions in disease-relevant cell types\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which maspardin loss of function leads to axonal degeneration in Mast syndrome remains uncharacterized; it is unknown whether maspardin regulates vesicular trafficking, lipid metabolism, or another endosomal process in long-tract neurons.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cargo or trafficking pathway has been identified as maspardin-dependent\",\n        \"No structural model of maspardin in complex with its partners exists\",\n        \"Neuronal cell-type–specific functions have not been investigated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0060090\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [1]\n      },\n      {\n        \"term_id\": \"GO:0005794\",\n        \"supporting_discovery_ids\": [1]\n      },\n      {\n        \"term_id\": \"GO:0005768\",\n        \"supporting_discovery_ids\": [1]\n      }\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD4\",\n      \"ALDH16A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Maspardin (SPG21/ACP33) is a cytoplasmic and trans-Golgi network/late endosomal protein that functions in intracellular protein transport and sorting [PMID:14564668, PMID:19184135]. It contains a noncatalytic alpha/beta hydrolase fold domain that mediates direct interaction with the cytoplasmic tail of CD4, negatively modulating CD4-dependent T cell costimulation [PMID:11113139]. Maspardin also binds the aldehyde dehydrogenase ALDH16A1, with which it colocalizes in endosomal/Golgi compartments [PMID:19184135]. A homozygous frameshift mutation in SPG21 (601insA) causes Mast syndrome, an autosomal recessive hereditary spastic paraplegia with dementia [PMID:14564668].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The first molecular function attributed to maspardin was as an intracellular negative regulator of CD4 signaling, establishing that its alpha/beta hydrolase fold domain mediates a direct protein–protein interaction rather than catalysis.\",\n      \"evidence\": \"Yeast two-hybrid screen, co-immunoprecipitation, deletion mutagenesis, and T cell activation assays in vitro\",\n      \"pmids\": [\"11113139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction identified in a single lab without independent replication\",\n        \"Endogenous complex stoichiometry and physiological relevance in primary T cells not established\",\n        \"Whether the hydrolase fold retains any residual catalytic activity remains untested\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Genetic mapping of Mast syndrome to SPG21 established maspardin as essential for neuronal maintenance and linked its loss to hereditary spastic paraplegia with dementia, placing the protein's transport/sorting function in a disease context.\",\n      \"evidence\": \"Positional cloning in an Amish pedigree with homozygous frameshift mutation (601insA) confirmed across 14 affected individuals\",\n      \"pmids\": [\"14564668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which loss of maspardin leads to corticospinal tract degeneration is unknown\",\n        \"No rescue experiment or animal model reported in this study\",\n        \"Specific cargo sorted by maspardin-containing vesicles not identified\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of ALDH16A1 as a maspardin binding partner expanded the protein's interactome beyond CD4 and suggested a functional connection between endosomal/Golgi trafficking and aldehyde metabolism.\",\n      \"evidence\": \"Immunoprecipitation followed by mass spectrometry, reciprocal co-IP of overexpressed proteins, fusion protein pull-down, and confocal colocalization\",\n      \"pmids\": [\"19184135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the maspardin–ALDH16A1 interaction is unknown\",\n        \"Interaction validated only with overexpressed or tagged proteins; endogenous validation at physiological levels lacking\",\n        \"Whether ALDH16A1 binding is relevant to the Mast syndrome phenotype is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise cargo(s) sorted by maspardin in endosomal/trans-Golgi trafficking, the structural basis of its protein interactions, and the cellular pathway connecting maspardin loss to neurodegeneration remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No animal or neuronal model characterizing maspardin loss-of-function phenotypes at the cellular level\",\n        \"No structural model of maspardin or its complexes\",\n        \"Relationship between the CD4 and ALDH16A1 interactions and neuronal function is unclear\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD4\",\n      \"ALDH16A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}