{"gene":"MFSD6L","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2024,"finding":"MFSD6L localizes to the acrosome membrane of sperm and is required for acrosome formation and sperm head shaping; it physically interacts with the inner acrosomal membrane protein SPACA1, and its loss causes deformed acrosomes, reduced sperm concentration and motility (oligoasthenoteratozoospermia) in both humans and Mfsd6l knockout mice.","method":"Bi-allelic loss-of-function variant identification in human patients, Mfsd6l knockout mouse model with sperm phenotyping, acrosome membrane localization by direct imaging/fractionation, protein-protein interaction with SPACA1 (co-immunoprecipitation/pulldown), and ICSI embryo development assay","journal":"Journal of genetics and genomics = Yi chuan xue bao","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction with SPACA1, KO mouse with defined cellular phenotype, human genetic validation, and functional ICSI assay across two independent species","pmids":["38909778"],"is_preprint":false},{"year":2012,"finding":"Recessive loss-of-function variants in MFSD6L were identified as a novel candidate cause of pediatric cataract in a Saudi Arabian cohort, suggesting a role for MFSD6L in lens development.","method":"Autozygome and exome analysis of 38 index patients with pediatric cataract","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Low","confidence_rationale":"Tier 4 — genomic association only, no functional mechanistic validation; authors note the finding requires independent confirmation","pmids":["22935719"],"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 disrupts acrosome formation and causes oligoasthenoteratozoospermia, and it has also been proposed as a candidate gene for pediatric cataract based on genomic evidence."},"narrative":{"teleology":[{"year":2012,"claim":"Genomic evidence first linked MFSD6L to human disease when recessive variants were identified as a candidate cause of pediatric cataract, raising the possibility that MFSD6L functions in lens development.","evidence":"Autozygome and exome sequencing in a Saudi Arabian pediatric cataract cohort","pmids":["22935719"],"confidence":"Low","gaps":["No functional validation or replication of the cataract association was performed","No mechanism linking MFSD6L to lens biology was proposed","Single cohort without independent confirmation"]},{"year":2024,"claim":"The primary biological function of MFSD6L was established as an acrosome membrane protein required for acrosome biogenesis and sperm head morphogenesis, resolving what the gene does at a cellular level and identifying its key binding partner SPACA1.","evidence":"Bi-allelic loss-of-function variants in infertile men, Mfsd6l knockout mouse with acrosome and sperm phenotyping, co-immunoprecipitation demonstrating MFSD6L–SPACA1 interaction, and ICSI rescue assay","pmids":["38909778"],"confidence":"High","gaps":["Structural basis of the MFSD6L–SPACA1 interaction is unknown","Whether MFSD6L retains transporter activity typical of the MFS superfamily has not been tested","Relationship, if any, between acrosomal function and the earlier cataract association remains unresolved"]},{"year":null,"claim":"It remains unknown whether MFSD6L functions as a membrane transporter, what cargo it might carry, and whether it has roles outside spermatogenesis (e.g., in the lens).","evidence":"","pmids":[],"confidence":"Low","gaps":["No transport activity or substrate has been identified","No structural model exists","The cataract association has not been functionally validated"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0043226","term_label":"organelle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["SPACA1"],"other_free_text":[]},"mechanistic_narrative":"MFSD6L is an acrosome membrane protein essential for acrosome formation and sperm head shaping, functioning through physical interaction with the inner acrosomal membrane protein SPACA1 [PMID:38909778]. Loss of MFSD6L in both humans (bi-allelic loss-of-function variants) and Mfsd6l knockout mice causes deformed acrosomes and oligoasthenoteratozoospermia, establishing it as a cause of male infertility [PMID:38909778]."},"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":53,"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":3338,"output_tokens":605,"usd":0.009544},"stage2":{"model":"claude-opus-4-6","input_tokens":3770,"output_tokens":840,"usd":0.059775},"total_usd":0.069319,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"MFSD6L localizes to the acrosome membrane of sperm and is required for acrosome formation and sperm head shaping; it physically interacts with the inner acrosomal membrane protein SPACA1, and its loss causes deformed acrosomes, reduced sperm concentration and motility (oligoasthenoteratozoospermia) in both humans and Mfsd6l knockout mice.\",\n      \"method\": \"Bi-allelic loss-of-function variant identification in human patients, Mfsd6l knockout mouse model with sperm phenotyping, acrosome membrane localization by direct imaging/fractionation, protein-protein interaction with SPACA1 (co-immunoprecipitation/pulldown), and ICSI embryo development assay\",\n      \"journal\": \"Journal of genetics and genomics = Yi chuan xue bao\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction with SPACA1, KO mouse with defined cellular phenotype, human genetic validation, and functional ICSI assay across two independent species\",\n      \"pmids\": [\"38909778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Recessive loss-of-function variants in MFSD6L were identified as a novel candidate cause of pediatric cataract in a Saudi Arabian cohort, suggesting a role for MFSD6L in lens development.\",\n      \"method\": \"Autozygome and exome analysis of 38 index patients with pediatric cataract\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genomic association only, no functional mechanistic validation; authors note the finding requires independent confirmation\",\n      \"pmids\": [\"22935719\"],\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 disrupts acrosome formation and causes oligoasthenoteratozoospermia, and it has also been proposed as a candidate gene for pediatric cataract based on genomic evidence.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MFSD6L is an acrosome membrane protein essential for acrosome formation and sperm head shaping, functioning through physical interaction with the inner acrosomal membrane protein SPACA1 [PMID:38909778]. Loss of MFSD6L in both humans (bi-allelic loss-of-function variants) and Mfsd6l knockout mice causes deformed acrosomes and oligoasthenoteratozoospermia, establishing it as a cause of male infertility [PMID:38909778].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Genomic evidence first linked MFSD6L to human disease when recessive variants were identified as a candidate cause of pediatric cataract, raising the possibility that MFSD6L functions in lens development.\",\n      \"evidence\": \"Autozygome and exome sequencing in a Saudi Arabian pediatric cataract cohort\",\n      \"pmids\": [\"22935719\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional validation or replication of the cataract association was performed\",\n        \"No mechanism linking MFSD6L to lens biology was proposed\",\n        \"Single cohort without independent confirmation\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The primary biological function of MFSD6L was established as an acrosome membrane protein required for acrosome biogenesis and sperm head morphogenesis, resolving what the gene does at a cellular level and identifying its key binding partner SPACA1.\",\n      \"evidence\": \"Bi-allelic loss-of-function variants in infertile men, Mfsd6l knockout mouse with acrosome and sperm phenotyping, co-immunoprecipitation demonstrating MFSD6L–SPACA1 interaction, and ICSI rescue assay\",\n      \"pmids\": [\"38909778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the MFSD6L–SPACA1 interaction is unknown\",\n        \"Whether MFSD6L retains transporter activity typical of the MFS superfamily has not been tested\",\n        \"Relationship, if any, between acrosomal function and the earlier cataract association remains unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether MFSD6L functions as a membrane transporter, what cargo it might carry, and whether it has roles outside spermatogenesis (e.g., in the lens).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No transport activity or substrate has been identified\",\n        \"No structural model exists\",\n        \"The cataract association has not been functionally validated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0043226\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1474165\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SPACA1\"],\n    \"other_free_text\": []\n  }\n}\n```"}