{"gene":"MFSD6L","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2024,"finding":"MFSD6L localizes to the acrosome membrane in sperm and is required for acrosome formation and sperm head shaping; it interacts with the inner acrosomal membrane protein SPACA1, and its loss (bi-allelic variants in humans; knockout in mice) causes oligoasthenoteratozoospermia with reduced sperm concentration, motility, and deformed acrosomes.","method":"Genetic analysis of human patients with bi-allelic loss-of-function variants, Mfsd6l knockout mouse model with phenotypic characterization, subcellular localization experiments identifying MFSD6L as an acrosome membrane protein, and co-immunoprecipitation/interaction studies with SPACA1","journal":"Journal of genetics and genomics = Yi chuan xue bao","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal human genetic + mouse KO with defined cellular phenotype, direct localization experiment with functional consequence, and protein–protein interaction with SPACA1 reported in a single focused study","pmids":["38909778"],"is_preprint":false}],"current_model":"MFSD6L is an acrosome membrane protein that anchors the sperm acrosome and shapes the sperm head by interacting with the inner acrosomal membrane protein SPACA1; loss of MFSD6L in humans and mice causes oligoasthenoteratozoospermia with deformed acrosomes, reduced sperm count, and impaired motility, leading to male subfertility."},"narrative":{"mechanistic_narrative":"MFSD6L is an acrosome membrane protein required for acrosome biogenesis and sperm head shaping during spermatogenesis [PMID:38909778]. It localizes to the sperm acrosome membrane and physically interacts with the inner acrosomal membrane protein SPACA1, supporting acrosome architecture and anchoring [PMID:38909778]. Loss of MFSD6L through bi-allelic loss-of-function variants in humans or gene knockout in mice causes oligoasthenoteratozoospermia, with reduced sperm concentration, impaired motility, and deformed acrosomes, linking MFSD6L deficiency to male subfertility [PMID:38909778]. Beyond this single focused study, no further mechanistic detail — including any transporter activity or molecular role outside the acrosome — has been characterized in the available corpus.","teleology":[{"year":2024,"claim":"Established that MFSD6L is an acrosome membrane protein whose loss disrupts acrosome formation and sperm head morphology, defining its role in spermatogenesis and male fertility.","evidence":"Human bi-allelic loss-of-function variant analysis, Mfsd6l knockout mouse phenotyping, subcellular localization to the acrosome membrane, and co-immunoprecipitation with SPACA1","pmids":["38909778"],"confidence":"High","gaps":["Molecular function of MFSD6L (e.g. any transport activity implied by its MFS-type name) is not defined","The mechanism by which MFSD6L–SPACA1 interaction shapes the acrosome is not resolved structurally","No reciprocal validation or mapped interaction interface for the SPACA1 binding is reported"]},{"year":null,"claim":"Whether MFSD6L has an intrinsic biochemical/transport activity and how it is recruited to and organizes the acrosomal membrane remains unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No substrate or transport assay has been reported","No structural model of MFSD6L or its complex with SPACA1","Role outside sperm, if any, is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["SPACA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWD5","full_name":"Major facilitator superfamily domain-containing protein 6-like","aliases":[],"length_aa":586,"mass_kda":64.0,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q8IWD5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MFSD6L","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MFSD6L","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":8.8},{"tissue":"testis","ntpm":23.6}],"url":"https://www.proteinatlas.org/search/MFSD6L"},"hgnc":{"alias_symbol":["SLC73A2","FLJ35773"],"prev_symbol":[]},"alphafold":{"accession":"Q8IWD5","domains":[{"cath_id":"1.20.1250,1.20.1250","chopping":"12-105_244-343","consensus_level":"medium","plddt":89.6331,"start":12,"end":343},{"cath_id":"1.20.1250.20","chopping":"353-546","consensus_level":"medium","plddt":92.0181,"start":353,"end":546}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWD5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWD5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWD5-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MFSD6L","jax_strain_url":"https://www.jax.org/strain/search?query=MFSD6L"},"sequence":{"accession":"Q8IWD5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWD5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWD5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWD5"}},"corpus_meta":[{"pmid":"22935719","id":"PMC_22935719","title":"Genomic analysis of pediatric cataract in Saudi Arabia reveals novel candidate disease genes.","date":"2012","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22935719","citation_count":55,"is_preprint":false},{"pmid":"26979619","id":"PMC_26979619","title":"Changes in gene methylation patterns in neonatal murine hearts: Implications for the regenerative potential.","date":"2016","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/26979619","citation_count":24,"is_preprint":false},{"pmid":"33134824","id":"PMC_33134824","title":"Epigenome-Wide Association Study Using Prediagnostic Bloods Identifies New Genomic Regions Associated With Pancreatic Cancer Risk.","date":"2020","source":"JNCI cancer spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/33134824","citation_count":12,"is_preprint":false},{"pmid":"38909778","id":"PMC_38909778","title":"Deficiency of MFSD6L, an acrosome membrane protein, causes oligoasthenoteratozoospermia in humans and mice.","date":"2024","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/38909778","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4107,"output_tokens":419,"usd":0.009303,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6684,"output_tokens":911,"usd":0.028098,"stage2_stop_reason":"end_turn"},"total_usd":0.037401,"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\": 2024,\n      \"finding\": \"MFSD6L localizes to the acrosome membrane in sperm and is required for acrosome formation and sperm head shaping; it interacts with the inner acrosomal membrane protein SPACA1, and its loss (bi-allelic variants in humans; knockout in mice) causes oligoasthenoteratozoospermia with reduced sperm concentration, motility, and deformed acrosomes.\",\n      \"method\": \"Genetic analysis of human patients with bi-allelic loss-of-function variants, Mfsd6l knockout mouse model with phenotypic characterization, subcellular localization experiments identifying MFSD6L as an acrosome membrane protein, and co-immunoprecipitation/interaction studies with SPACA1\",\n      \"journal\": \"Journal of genetics and genomics = Yi chuan xue bao\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal human genetic + mouse KO with defined cellular phenotype, direct localization experiment with functional consequence, and protein–protein interaction with SPACA1 reported in a single focused study\",\n      \"pmids\": [\"38909778\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MFSD6L is an acrosome membrane protein that anchors the sperm acrosome and shapes the sperm head by interacting with the inner acrosomal membrane protein SPACA1; loss of MFSD6L in humans and mice causes oligoasthenoteratozoospermia with deformed acrosomes, reduced sperm count, and impaired motility, leading to male subfertility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MFSD6L is an acrosome membrane protein required for acrosome biogenesis and sperm head shaping during spermatogenesis [#0]. It localizes to the sperm acrosome membrane and physically interacts with the inner acrosomal membrane protein SPACA1, supporting acrosome architecture and anchoring [#0]. Loss of MFSD6L through bi-allelic loss-of-function variants in humans or gene knockout in mice causes oligoasthenoteratozoospermia, with reduced sperm concentration, impaired motility, and deformed acrosomes, linking MFSD6L deficiency to male subfertility [#0]. Beyond this single focused study, no further mechanistic detail — including any transporter activity or molecular role outside the acrosome — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that MFSD6L is an acrosome membrane protein whose loss disrupts acrosome formation and sperm head morphology, defining its role in spermatogenesis and male fertility.\",\n      \"evidence\": \"Human bi-allelic loss-of-function variant analysis, Mfsd6l knockout mouse phenotyping, subcellular localization to the acrosome membrane, and co-immunoprecipitation with SPACA1\",\n      \"pmids\": [\"38909778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular function of MFSD6L (e.g. any transport activity implied by its MFS-type name) is not defined\",\n        \"The mechanism by which MFSD6L–SPACA1 interaction shapes the acrosome is not resolved structurally\",\n        \"No reciprocal validation or mapped interaction interface for the SPACA1 binding is reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether MFSD6L has an intrinsic biochemical/transport activity and how it is recruited to and organizes the acrosomal membrane remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No substrate or transport assay has been reported\",\n        \"No structural model of MFSD6L or its complex with SPACA1\",\n        \"Role outside sperm, if any, is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SPACA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}