{"gene":"FAM149B1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2019,"finding":"Loss-of-function mutations in FAM149B1 in patient fibroblasts cause abnormal accumulation of IFT complex at distal ciliary tips (bulbous appearance), increased primary cilium length, and dysregulated SHH signaling, while ciliogenesis itself remains normal.","method":"Patient-derived mutant fibroblast analysis (immunofluorescence for IFT complex localization, cilia length measurement, SHH signaling assay)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cellular phenotype in patient-derived cells with multiple readouts (IFT accumulation, cilia length, SHH signaling), single lab","pmids":["30905400"],"is_preprint":false},{"year":2022,"finding":"FAM149B1 physically interacts with both BROMI/TBC1D32 and CCRK/CDK20, placing it in a complex that regulates IFT turnaround at the ciliary tip; FAM149B1-knockout cells display abnormally long cilia and accumulation of IFT machinery and ICK/CILK1 at the ciliary tip, phenocopying BROMI-KO and CCRK-KO cells.","method":"Co-immunoprecipitation (direct interaction with CCRK and BROMI), knockout cell line generation with ciliary phenotype analysis (immunofluorescence for IFT machinery and ICK localization, cilia length measurement)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing direct interactions with CCRK and BROMI, KO cells with defined ciliary phenotypes, replicated across multiple KO lines in same study","pmids":["35609210"],"is_preprint":false},{"year":2021,"finding":"XBX-4, the C. elegans FAM149B1 homolog (DUF3719 domain), acts upstream in the DYF-18 CCRK / DYF-5 MAK kinase pathway to regulate cilia length and axonemal microtubule stability; loss of xbx-4 elongates sensory neuron cilia with stabilized axonemal MTs, and XBX-4 promotes DYF-18 CCRK function to regulate localization and activity of DYF-5 MAK. Joubert syndrome-associated mutations in the DUF3719 domain also elongate cilia in C. elegans.","method":"C. elegans genetic epistasis (double mutants with dyf-18 and dyf-5), cilia length and MT stability assays, kinase localization/function analysis in xbx-4 mutant background, expression of human disease-variant alleles","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in multiple allelic backgrounds, replicated across kinase pathway members, disease-variant functional validation in vivo","pmids":["34731674"],"is_preprint":false}],"current_model":"FAM149B1 (JBTS36) is a ciliary protein containing a DUF3719 domain that physically associates with BROMI/TBC1D32 and CCRK/CDK20 to regulate IFT machinery turnaround at the ciliary tip, acting upstream in the CCRK–ICK/MAK kinase cascade; its loss causes abnormally elongated cilia with IFT complex and ICK accumulation at ciliary tips, stabilized axonemal microtubules, and dysregulated SHH signaling, collectively producing Joubert syndrome ciliopathy phenotypes."},"narrative":{"mechanistic_narrative":"FAM149B1 (JBTS36) is a ciliary regulatory protein that controls intraflagellar transport (IFT) turnaround at the ciliary tip and thereby sets primary cilium length and Sonic hedgehog signaling output [PMID:30905400, PMID:35609210]. It physically associates with BROMI/TBC1D32 and the kinase CCRK/CDK20, placing it within a complex that governs IFT machinery dynamics at the distal cilium [PMID:35609210]. FAM149B1 acts upstream in the CCRK–ICK/MAK kinase cascade: its homolog XBX-4 in C. elegans promotes CCRK (DYF-18) function to control the localization and activity of the downstream kinase MAK (DYF-5), regulating axonemal microtubule stability [PMID:34731674]. Loss of FAM149B1 leaves ciliogenesis intact but causes abnormally elongated cilia with accumulation of IFT complexes and the kinase ICK/CILK1 at the ciliary tip, phenocopying BROMI- and CCRK-knockout cells [PMID:30905400, PMID:35609210]. Joubert syndrome-associated mutations map to its conserved DUF3719 domain and recapitulate cilia elongation in vivo, establishing FAM149B1 loss of function as a cause of this ciliopathy [PMID:30905400, PMID:34731674].","teleology":[{"year":2019,"claim":"Establishing whether FAM149B1 has a ciliary function, this work showed that patient loss-of-function mutations disrupt IFT distribution rather than cilium formation, defining the gene as a regulator of IFT turnaround and cilium length.","evidence":"Immunofluorescence, cilia length measurement, and SHH signaling assays in patient-derived mutant fibroblasts","pmids":["30905400"],"confidence":"Medium","gaps":["Single-lab cellular phenotype without molecular partners identified","Mechanism linking IFT tip accumulation to SHH dysregulation not resolved","No direct demonstration of the affected kinase pathway"]},{"year":2021,"claim":"To place FAM149B1 in a defined signaling hierarchy, genetic epistasis in C. elegans positioned the homolog XBX-4 upstream of the CCRK–MAK kinase cascade controlling cilia length and axonemal microtubule stability, and validated that disease-variant alleles are functionally pathogenic in vivo.","evidence":"C. elegans double-mutant epistasis with dyf-18/dyf-5, microtubule stability assays, and expression of human disease-variant alleles","pmids":["34731674"],"confidence":"High","gaps":["How XBX-4/FAM149B1 promotes CCRK function biochemically is unknown","Conservation of the precise kinase regulatory step to mammals not directly shown in this work"]},{"year":2022,"claim":"To define the physical basis of FAM149B1's regulatory role, reciprocal Co-IP demonstrated direct interaction with BROMI/TBC1D32 and CCRK/CDK20, and knockout cells showed IFT and ICK/CILK1 accumulation at the tip, unifying FAM149B1 with the BROMI/CCRK complex controlling IFT turnaround.","evidence":"Reciprocal co-immunoprecipitation and knockout cell lines with IFT/ICK localization and cilia length analysis","pmids":["35609210"],"confidence":"High","gaps":["Stoichiometry and architecture of the FAM149B1–BROMI–CCRK complex not resolved","Whether FAM149B1 directly modulates CCRK catalytic activity is not established","No structural model of the DUF3719 domain's interactions"]},{"year":null,"claim":"The biochemical mechanism by which FAM149B1 promotes CCRK activity and triggers IFT turnaround at the ciliary tip remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No enzymatic or molecular activity assigned to FAM149B1 itself","Mechanism converting tip-localized kinase signaling into IFT turnaround unknown","Structural basis of DUF3719-mediated complex assembly undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]}],"complexes":[],"partners":["TBC1D32","CDK20"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96BN6","full_name":"Primary cilium assembly protein FAM149B1","aliases":[],"length_aa":582,"mass_kda":64.6,"function":"Involved in the localization of proteins to the cilium and cilium assembly. Indirectly regulates the signaling functions of the cilium, being required for normal SHH/smoothened signaling and proper development","subcellular_location":"Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q96BN6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM149B1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FAM149B1","total_profiled":1310},"omim":[{"mim_id":"618763","title":"JOUBERT SYNDROME 36; JBTS36","url":"https://www.omim.org/entry/618763"},{"mim_id":"618413","title":"FAMILY WITH SEQUENCE SIMILARITY 149, MEMBER B1; FAM149B1","url":"https://www.omim.org/entry/618413"},{"mim_id":"213300","title":"JOUBERT SYNDROME 1; JBTS1","url":"https://www.omim.org/entry/213300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM149B1"},"hgnc":{"alias_symbol":[],"prev_symbol":["KIAA0974"]},"alphafold":{"accession":"Q96BN6","domains":[{"cath_id":"1.10.1390","chopping":"97-136","consensus_level":"medium","plddt":84.662,"start":97,"end":136}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BN6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BN6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BN6-F1-predicted_aligned_error_v6.png","plddt_mean":51.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM149B1","jax_strain_url":"https://www.jax.org/strain/search?query=FAM149B1"},"sequence":{"accession":"Q96BN6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BN6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BN6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BN6"}},"corpus_meta":[{"pmid":"30905400","id":"PMC_30905400","title":"Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30905400","citation_count":27,"is_preprint":false},{"pmid":"35609210","id":"PMC_35609210","title":"BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1.","date":"2022","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/35609210","citation_count":12,"is_preprint":false},{"pmid":"34731674","id":"PMC_34731674","title":"xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and RCK kinase cascade to regulate cilia morphology.","date":"2021","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/34731674","citation_count":8,"is_preprint":false},{"pmid":"42064743","id":"PMC_42064743","title":"Joubert syndrome gene fam149b1 homolog, xbx-4 , is required for multiple sensory behaviors.","date":"2026","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/42064743","citation_count":0,"is_preprint":false},{"pmid":"40205804","id":"PMC_40205804","title":"Comprehensive Proteomics and Machine Learning Analysis to Distinguish Follicular Adenoma and Follicular Thyroid Carcinoma from Indeterminate Thyroid Nodules.","date":"2025","source":"Endocrinology and metabolism (Seoul, Korea)","url":"https://pubmed.ncbi.nlm.nih.gov/40205804","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4717,"output_tokens":1000,"usd":0.014575,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7487,"output_tokens":1770,"usd":0.040842,"stage2_stop_reason":"end_turn"},"total_usd":0.055417,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function mutations in FAM149B1 in patient fibroblasts cause abnormal accumulation of IFT complex at distal ciliary tips (bulbous appearance), increased primary cilium length, and dysregulated SHH signaling, while ciliogenesis itself remains normal.\",\n      \"method\": \"Patient-derived mutant fibroblast analysis (immunofluorescence for IFT complex localization, cilia length measurement, SHH signaling assay)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cellular phenotype in patient-derived cells with multiple readouts (IFT accumulation, cilia length, SHH signaling), single lab\",\n      \"pmids\": [\"30905400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM149B1 physically interacts with both BROMI/TBC1D32 and CCRK/CDK20, placing it in a complex that regulates IFT turnaround at the ciliary tip; FAM149B1-knockout cells display abnormally long cilia and accumulation of IFT machinery and ICK/CILK1 at the ciliary tip, phenocopying BROMI-KO and CCRK-KO cells.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction with CCRK and BROMI), knockout cell line generation with ciliary phenotype analysis (immunofluorescence for IFT machinery and ICK localization, cilia length measurement)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing direct interactions with CCRK and BROMI, KO cells with defined ciliary phenotypes, replicated across multiple KO lines in same study\",\n      \"pmids\": [\"35609210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"XBX-4, the C. elegans FAM149B1 homolog (DUF3719 domain), acts upstream in the DYF-18 CCRK / DYF-5 MAK kinase pathway to regulate cilia length and axonemal microtubule stability; loss of xbx-4 elongates sensory neuron cilia with stabilized axonemal MTs, and XBX-4 promotes DYF-18 CCRK function to regulate localization and activity of DYF-5 MAK. Joubert syndrome-associated mutations in the DUF3719 domain also elongate cilia in C. elegans.\",\n      \"method\": \"C. elegans genetic epistasis (double mutants with dyf-18 and dyf-5), cilia length and MT stability assays, kinase localization/function analysis in xbx-4 mutant background, expression of human disease-variant alleles\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in multiple allelic backgrounds, replicated across kinase pathway members, disease-variant functional validation in vivo\",\n      \"pmids\": [\"34731674\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM149B1 (JBTS36) is a ciliary protein containing a DUF3719 domain that physically associates with BROMI/TBC1D32 and CCRK/CDK20 to regulate IFT machinery turnaround at the ciliary tip, acting upstream in the CCRK–ICK/MAK kinase cascade; its loss causes abnormally elongated cilia with IFT complex and ICK accumulation at ciliary tips, stabilized axonemal microtubules, and dysregulated SHH signaling, collectively producing Joubert syndrome ciliopathy phenotypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM149B1 (JBTS36) is a ciliary regulatory protein that controls intraflagellar transport (IFT) turnaround at the ciliary tip and thereby sets primary cilium length and Sonic hedgehog signaling output [#0, #1]. It physically associates with BROMI/TBC1D32 and the kinase CCRK/CDK20, placing it within a complex that governs IFT machinery dynamics at the distal cilium [#1]. FAM149B1 acts upstream in the CCRK–ICK/MAK kinase cascade: its homolog XBX-4 in C. elegans promotes CCRK (DYF-18) function to control the localization and activity of the downstream kinase MAK (DYF-5), regulating axonemal microtubule stability [#2]. Loss of FAM149B1 leaves ciliogenesis intact but causes abnormally elongated cilia with accumulation of IFT complexes and the kinase ICK/CILK1 at the ciliary tip, phenocopying BROMI- and CCRK-knockout cells [#0, #1]. Joubert syndrome-associated mutations map to its conserved DUF3719 domain and recapitulate cilia elongation in vivo, establishing FAM149B1 loss of function as a cause of this ciliopathy [#0, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing whether FAM149B1 has a ciliary function, this work showed that patient loss-of-function mutations disrupt IFT distribution rather than cilium formation, defining the gene as a regulator of IFT turnaround and cilium length.\",\n      \"evidence\": \"Immunofluorescence, cilia length measurement, and SHH signaling assays in patient-derived mutant fibroblasts\",\n      \"pmids\": [\"30905400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab cellular phenotype without molecular partners identified\",\n        \"Mechanism linking IFT tip accumulation to SHH dysregulation not resolved\",\n        \"No direct demonstration of the affected kinase pathway\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"To place FAM149B1 in a defined signaling hierarchy, genetic epistasis in C. elegans positioned the homolog XBX-4 upstream of the CCRK–MAK kinase cascade controlling cilia length and axonemal microtubule stability, and validated that disease-variant alleles are functionally pathogenic in vivo.\",\n      \"evidence\": \"C. elegans double-mutant epistasis with dyf-18/dyf-5, microtubule stability assays, and expression of human disease-variant alleles\",\n      \"pmids\": [\"34731674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How XBX-4/FAM149B1 promotes CCRK function biochemically is unknown\",\n        \"Conservation of the precise kinase regulatory step to mammals not directly shown in this work\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"To define the physical basis of FAM149B1's regulatory role, reciprocal Co-IP demonstrated direct interaction with BROMI/TBC1D32 and CCRK/CDK20, and knockout cells showed IFT and ICK/CILK1 accumulation at the tip, unifying FAM149B1 with the BROMI/CCRK complex controlling IFT turnaround.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and knockout cell lines with IFT/ICK localization and cilia length analysis\",\n      \"pmids\": [\"35609210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and architecture of the FAM149B1–BROMI–CCRK complex not resolved\",\n        \"Whether FAM149B1 directly modulates CCRK catalytic activity is not established\",\n        \"No structural model of the DUF3719 domain's interactions\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which FAM149B1 promotes CCRK activity and triggers IFT turnaround at the ciliary tip remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No enzymatic or molecular activity assigned to FAM149B1 itself\",\n        \"Mechanism converting tip-localized kinase signaling into IFT turnaround unknown\",\n        \"Structural basis of DUF3719-mediated complex assembly undetermined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TBC1D32\", \"CDK20\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}