--- provider: falcon model: Edison Scientific Literature cached: false start_time: '2026-06-13T06:40:16.234964' end_time: '2026-06-13T06:48:09.338466' duration_seconds: 473.1 template_file: templates/gene_research_go_focused.md template_variables: organism: human gene_id: FBXO41 gene_symbol: FBXO41 uniprot_accession: Q8TF61 protein_description: 'RecName: Full=F-box only protein 41;' gene_info: Name=FBXO41; Synonyms=FBX41, KIAA1940; organism_full: Homo sapiens (Human). protein_family: Not specified in UniProt protein_domains: F-box-like_dom_sf. (IPR036047); F-box_dom. (IPR001810); FBX41/ZN365_Znf-C2H2. (IPR057038); GenomicStab_NeuMorph_Reg. (IPR052283); LRR_dom_sf. (IPR032675) provider_config: timeout: null max_retries: 3 parameters: allowed_domains: [] temperature: 0.1 max_embedded_images: 8 citation_count: 16 artifact_count: 1 artifact_sources: edison_answer_artifacts: 1 artifacts: - filename: artifact-00.md path: FBXO41-deep-research-falcon_artifacts/artifact-00.md media_type: text/markdown source: edison_answer_artifacts data_storage_id: null description: Edison artifact artifact-00 --- ## Question # Gene Research for Functional Annotation ## ⚠️ CRITICAL: Gene/Protein Identification Context **BEFORE YOU BEGIN RESEARCH:** You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms. ### Target Gene/Protein Identity (from UniProt): - **UniProt Accession:** Q8TF61 - **Protein Description:** RecName: Full=F-box only protein 41; - **Gene Information:** Name=FBXO41; Synonyms=FBX41, KIAA1940; - **Organism (full):** Homo sapiens (Human). - **Protein Family:** Not specified in UniProt - **Key Domains:** F-box-like_dom_sf. (IPR036047); F-box_dom. (IPR001810); FBX41/ZN365_Znf-C2H2. (IPR057038); GenomicStab_NeuMorph_Reg. (IPR052283); LRR_dom_sf. (IPR032675) ### MANDATORY VERIFICATION STEPS: 1. **Check if the gene symbol "FBXO41" matches the protein description above** 2. **Verify the organism is correct:** Homo sapiens (Human). 3. **Check if protein family/domains align with what you find in literature** 4. **If you find literature for a DIFFERENT gene with the same or similar symbol, STOP** ### If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature: **DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE.** Instead: - State clearly: "The gene symbol 'FBXO41' is ambiguous or literature is limited for this specific protein" - Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism") - Describe the protein based ONLY on the UniProt information provided above - Suggest that the protein function can be inferred from domain/family information ### Research Target: Please provide a comprehensive research report on the gene **FBXO41** (gene ID: FBXO41, UniProt: Q8TF61) in human. The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims. You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway. We are interested in where in or outside the cell the gene product carries out its function. We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role. Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available. ## Output Question: You are an expert researcher providing comprehensive, well-cited information. Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims. # Gene Research for Functional Annotation ## ⚠️ CRITICAL: Gene/Protein Identification Context **BEFORE YOU BEGIN RESEARCH:** You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms. ### Target Gene/Protein Identity (from UniProt): - **UniProt Accession:** Q8TF61 - **Protein Description:** RecName: Full=F-box only protein 41; - **Gene Information:** Name=FBXO41; Synonyms=FBX41, KIAA1940; - **Organism (full):** Homo sapiens (Human). - **Protein Family:** Not specified in UniProt - **Key Domains:** F-box-like_dom_sf. (IPR036047); F-box_dom. (IPR001810); FBX41/ZN365_Znf-C2H2. (IPR057038); GenomicStab_NeuMorph_Reg. (IPR052283); LRR_dom_sf. (IPR032675) ### MANDATORY VERIFICATION STEPS: 1. **Check if the gene symbol "FBXO41" matches the protein description above** 2. **Verify the organism is correct:** Homo sapiens (Human). 3. **Check if protein family/domains align with what you find in literature** 4. **If you find literature for a DIFFERENT gene with the same or similar symbol, STOP** ### If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature: **DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE.** Instead: - State clearly: "The gene symbol 'FBXO41' is ambiguous or literature is limited for this specific protein" - Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism") - Describe the protein based ONLY on the UniProt information provided above - Suggest that the protein function can be inferred from domain/family information ### Research Target: Please provide a comprehensive research report on the gene **FBXO41** (gene ID: FBXO41, UniProt: Q8TF61) in human. The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims. You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway. We are interested in where in or outside the cell the gene product carries out its function. We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role. Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available. ## Comprehensive Research Report: Human **FBXO41** (UniProt **Q8TF61**) — Functional Annotation, Biology, and Recent Research ### 0) Scope and identity verification (mandatory) FBXO41 (F-box only protein 41; synonyms **FBX41, KIAA1940**) is a human F-box protein reported as an ~875 aa protein with a canonical F-box domain, consistent with the UniProt target **Q8TF61** and its interpretation as a substrate-recognition/adaptor component of Cullin–RING ubiquitin ligases (CRLs), especially SCF/CRL1-type complexes. The sources used here explicitly refer to FBXO41/F-box protein 41 and are not attributable to a different gene with a similar symbol. (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) ### 1) Key concepts and current understanding #### 1.1 F-box proteins and SCF/CRL biology (definitions) F-box proteins are typically substrate receptors in SCF ubiquitin ligases (Skp1–Cullin1–F-box), where the F-box domain mediates interaction with **SKP1** and thereby recruits the substrate receptor into a **CUL1**-based CRL. This architecture is consistent with how FBXO41 is experimentally characterized in cell systems (association with SKP1/CUL1, dependence on an intact F-box). (king2019fbxo41promotesdisassembly pages 2-3) #### 1.2 Current mechanistic model for FBXO41 The best-supported mechanistic model is that FBXO41 functions as an E3 ligase adaptor/substrate receptor that can assemble into an **SCF (SKP1–CUL1)** complex and, when enriched at neuronal centrosomes/centrioles, regulates primary cilium structure and associated signaling. Deleting or mutating the F-box domain abolishes SKP1/CUL1 binding, supporting the interpretation that FBXO41’s biological effects are coupled to CRL assembly. (king2019fbxo41promotesdisassembly pages 2-3) A second, less widely replicated model (presented in thesis-level work) proposes that FBXO41 can also participate in a **FBXO41–CUL7** E3 ligase complex in the nervous system, with proposed non-proteolytic ubiquitination of a neuronal cytoskeletal substrate (neurofilament medium). This suggests FBXO41 may have multiple Cullin contexts depending on cell state/compartment, but the SCF/CRL1 connection is the most directly demonstrated in the peer-reviewed cilia work. (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156) ### 2) Molecular function, domains, and substrate/partner evidence #### 2.1 Domains (what is known from the literature corpus retrieved here) A human genetics/characterization study reports FBXO41 as an 875-aa F-box protein, with InterProScan predicting a canonical **F-box** in the C-terminal half; the N-terminus was discussed as having an “apolipophorin III-like” region in earlier reports, though structural modeling was limited by lack of templates. These domain-level features support an adaptor role in ubiquitin ligase systems but do not identify a catalytic reaction (FBXO41 is not an enzyme catalytic subunit). (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) #### 2.2 SCF assembly and interactors In neuronal/cell models, FBXO41 associates with **SKP1** and **CUL1** (SCF complex components). Removing the F-box (Fbxo41ΔF-box) or introducing an F-box point mutation (W577A) abolishes SKP1/CUL1 interactions, indicating the F-box is required for SCF recruitment. (king2019fbxo41promotesdisassembly pages 2-3) #### 2.3 Proposed substrates/partners (strength of evidence) * **Strong experimental evidence (complex components):** SKP1, CUL1 association and F-box dependence. (king2019fbxo41promotesdisassembly pages 2-3) * **Moderate / preliminary evidence (thesis-level; neuronal biology):** FBXO41–CUL7 complex; proposed interaction with **DISC1** (and possibly **NDEL1**); proposed non-proteolytic **K63-linked ubiquitination** of **neurofilament medium (NFM)**. (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156) Importantly, a definitive, broadly validated human substrate repertoire for FBXO41 is not established in the retrieved literature; the most robust mechanistic readouts relate to centrosomal targeting and cilia phenotypes rather than identified ubiquitination substrates. (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) ### 3) Subcellular localization and where FBXO41 acts #### 3.1 Cytoplasmic and centrosomal/centriolar localization Mouse studies report FBXO41 is cytoplasmic and excluded from nucleus, and localizes prominently near the nucleus at the **centrosome** (pericentrin-positive). FBXO41 can be recovered with centrosome-enriched fractions, supporting authentic centrosomal association. (mukherjee2015lossofthe pages 4-4) In the cilia-disassembly study, endogenous and overexpressed FBXO41 localizes to the pericentriolar/centriolar region in neurons; super-resolution imaging places it adjacent to centriole markers, supporting centriolar positioning as a functional compartment for regulating cilia structure. (king2019fbxo41promotesdisassembly pages 2-3) #### 3.2 Targeting requirements Centrosomal targeting requires both **coiled-coil and F-box** domains; importantly, a centrosome-localized mutant lacking the F-box does not recapitulate cilia shortening, suggesting that localization alone is insufficient and that SCF assembly (or other F-box-dependent interactions) is required. (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 3-5) ### 4) Biological processes and pathways #### 4.1 Primary cilia disassembly and ciliary signaling (most mechanistically detailed) A peer-reviewed 2019 study identifies Fbxo41 as an SCF complex subunit that targets neuronal centrioles; increased centriolar accumulation of Fbxo41 **promotes primary cilia disassembly/shortening** and affects **Sonic hedgehog (Shh)** signaling, a canonical ciliary pathway. Levels of centrosomal Fbxo41 inversely correlate with cilia length, and disrupting SCF assembly or centrosome targeting disrupts function. (King et al., *Scientific Reports*, publication year 2019; URL https://doi.org/10.1038/s41598-019-44589-2) (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) Mechanistically, Fbxo41-dependent cilia disassembly requires **actin cytoskeleton rearrangements** in both mitotic and post-mitotic cells, and requires **Aurora A kinase** activation only in mitotic contexts—highlighting that the same adaptor can couple into distinct cilia disassembly circuitry depending on cell-cycle state. (king2019fbxo41promotesdisassembly pages 1-2) Key experimental timing/statistics: neuronal infections at **DIV1→DIV15** (to assess developing ciliogenesis) and **DIV13→DIV21** (to assess disassembly after ciliogenesis) both supported a disassembly role. Knockdown was effective but did not change basal cilia parameters under the tested conditions, emphasizing that overexpression/centrosomal enrichment is a major driver in their system. (king2019fbxo41promotesdisassembly pages 3-5, king2019fbxo41promotesdisassembly pages 2-3) #### 4.2 Neuronal migration and cerebellar development Mouse knockout and developmental studies support a role for FBXO41 in cerebellar development. Loss of Fbxo41 produces an ataxia-like phenotype with neuronal migration defects and cerebellar degeneration. FBXO41 is detected early in embryogenesis (E10) and is abundant postnatally in cerebellum; it is not detected in astrocytes or oligodendrocytes in those studies, supporting neuron-enriched expression. (Mukherjee et al., *Journal of Neuroscience*, 2015; URL https://doi.org/10.1523/jneurosci.2133-14.2015) (mukherjee2015lossofthe pages 4-4) Thesis-level work further argues that cytoplasmic FBXO41 is necessary and sufficient to stimulate cerebellar granule neuron migration, linking compartment-specific pools (cytoplasmic vs centrosomal) to distinct developmental outputs. (mukherjee2015functionalanalysisof pages 142-144) #### 4.3 Axon growth and neuronal cytoskeleton (proposed) The 2015 dissertation proposes that FBXO41–CUL7 mediates **K63-linked polyubiquitination** of NFM in a non-proteolytic manner to stabilize NFM and promote axon growth, and also suggests interactions with DISC1 and possibly NDEL1. These claims provide a plausible mechanistic bridge between ubiquitin signaling and neuronal morphogenesis but should be treated as less established than the SCF/CUL1 cilia findings because they are not presented here as a peer-reviewed primary article. (mukherjee2015functionalanalysisof pages 153-156, mukherjee2015functionalanalysisof pages 142-144) ### 5) Human genetics, disease associations, and interpretation #### 5.1 Rare-variant evidence A 2014 human study reports a novel homozygous FBXO41 variant **c.950G>A (p.Arg317Gln)** segregating with affected family members and absent from **400 control chromosomes**. Multiple prediction metrics were reported as consistent with deleteriousness (e.g., PolyPhen2 ~0.99; MutationTaster ~0.99; GERP++ 5.17), though SIFT was reported as tolerated (0.15). This provides suggestive but not definitive evidence that FBXO41 disruption can contribute to a neurodevelopmental/neurologic phenotype in humans. (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) #### 5.2 Curated disease-target associations (Open Targets) Open Targets lists FBXO41 associations to movement/ataxia-related disease concepts (e.g., generalized dystonia; infantile-onset autosomal recessive nonprogressive cerebellar ataxia; dysequilibrium syndrome), with modest overall association scores (example shown ~0.19 for generalized dystonia) and evidence largely traceable to the cerebellar/ataxia literature. (OpenTargets Search: -FBXO41) #### 5.3 2024 epigenetic evidence in 22q11.2 deletion syndrome (recent development) A June 2024 medRxiv preprint studying DNA methylation in **22q11.2 deletion syndrome (22q11.2DS)** reported FBXO41 as one of 15 genes consistent with a previously described episignature. In their comparison of **14 22q11.2DS patients vs 14 matched controls**, FBXO41 showed **14 significant differentially methylated positions (DMPs)** and a detected differentially methylated region (DMR) located on **exon 2** that was **hypermethylated** in 22q11.2DS. This positions FBXO41 as an epigenetically altered locus in a high-risk neuropsychiatric syndrome background, although methylation changes do not directly establish FBXO41 as a causal gene for schizophrenia or other 22q11.2DS phenotypes. (Jiao et al., medRxiv; posted June 24, 2024; URL https://doi.org/10.1101/2024.06.23.24309352) (jiao2024epigeneticfactorsin pages 10-13, jiao2024epigeneticfactorsin pages 7-10) ### 6) Current applications and real-world implementations #### 6.1 FBXO41 as a mechanistic handle in neurobiology (research implementation) The most concrete “real-world” implementation is as a research target for dissecting neuronal centrosome/cilium biology and cilia-dependent signaling (e.g., Shh pathway modulation) in primary neuron culture and epithelial cilia models. The 2019 study also uses pharmacologic perturbations (e.g., actin modulation; Aurora A pathway modulation) to probe mechanism and rescue phenotypes, demonstrating tractable experimental levers for FBXO41-dependent cilia dynamics. (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) #### 6.2 Biomarker/omics context (emerging but indirect) FBXO41 appears in recent multi-gene cancer/omics analyses (e.g., renal cancer panels) in which higher expression can correlate with poorer overall survival in univariate tests, but without evidence of FBXO41 as an independent predictor or mechanistic driver in the provided excerpts. Thus, at present FBXO41’s “application” in oncology is primarily as a candidate feature in bioinformatic signatures rather than an established biomarker or drug target. (yang2025fboxproteinfbxo21 pages 4-5) #### 6.3 Drug discovery relevance (conceptual) Because FBXO41 is a **substrate receptor** rather than a catalytic enzyme, translational strategies—if pursued—would likely involve (i) modulating its recruitment to centrioles/centrosomes, (ii) disrupting its interaction with SCF components, or (iii) targeting downstream substrates/pathways (e.g., actin/Aurora A-dependent cilia disassembly machinery). However, no FBXO41-directed drugs or clinical trials were identified in the retrieved evidence set. (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) ### 7) Expert analysis: what is well established vs uncertain **Most reliable, mechanistically supported claims (peer-reviewed):** * FBXO41 assembles into SCF/CRL1 complexes via SKP1/CUL1 in a F-box-dependent manner and targets neuronal centrosomes/centrioles. (king2019fbxo41promotesdisassembly pages 2-3) * Increased centrosomal FBXO41 promotes neuronal primary cilia disassembly/shortening and perturbs Shh signaling, with dependence on actin remodeling and context-dependent Aurora A involvement. (king2019fbxo41promotesdisassembly pages 1-2) **Strong phenotypic evidence (in vivo mouse):** * Fbxo41 loss leads to cerebellar migration defects, ataxia-like phenotypes, and neurodegeneration; FBXO41 is neuron-enriched and developmentally regulated in brain. (mukherjee2015lossofthe pages 4-4) **Promising but less mature areas:** * Specific ubiquitination substrates (e.g., NFM K63-ubiquitination) and alternative Cullin usage (CUL7) require more independent replication in peer-reviewed primary literature. (mukherjee2015functionalanalysisof pages 153-156) * Human disease causality remains suggestive (segregating variant; curated disease mappings; methylation signatures) but not definitively established for specific clinical syndromes based on the evidence retrieved here. (gregianin2014identificationandcharacterisationa pages 80-83, OpenTargets Search: -FBXO41, jiao2024epigeneticfactorsin pages 10-13) ### 8) Summary table The following table consolidates identity, mechanisms, localization, processes, interaction/substrate evidence, and disease/omics findings. | Aspect | FBXO41-specific finding | Evidence type | Organism/system | Key quantitative/statistical notes | Citations | |---|---|---|---|---|---| | Identity verification | Target matches **human FBXO41 / F-box only protein 41**, UniProt **Q8TF61**; reported as an **875-aa F-box protein** with higher expression in nervous system, helping distinguish it from unrelated FBX genes | Human genetic / bioinformatic annotation | Human | Gregianin reports FBXO41 as 1 of 46 F-box family members; transcript/protein identifiers linked to human FBXO41 | (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) | | Domain architecture | Canonical **F-box domain** in the C-terminal half supports SCF-type adaptor role; literature also reports an N-terminal **apolipophorin III-like** region, while newer domain resources/UniProt list F-box-like and LRR-related signatures | Bioinformatic / domain inference | Human | Domain inference used to support ubiquitin-ligase adaptor hypothesis; N-terminal structure remained poorly templated in 2014 analysis | (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) | | Proposed molecular function | FBXO41 behaves as an **SCF/CRL substrate adaptor**: associates with **SKP1** and **CUL1**; deletion or mutation of the F-box abolishes these interactions | Cell biology / biochemical interaction | Mouse protein in neuronal cells and hTERT-RPE1 model | FBXO41 assembles with SCF “less efficiently than Fbxo21”; **ΔF-box** or **W577A** disrupts SKP1/CUL1 binding | (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) | | Alternative ligase complex model | Separate mouse work proposes a **FBXO41–CUL7** E3 ligase complex in CNS neurons, implying FBXO41 may not be limited to canonical CRL1/SCF usage | Mouse functional study / thesis-level evidence | Mouse cerebellar granule neurons | Evidence is mechanistic but less independently validated than SCF/CUL1 data | (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156) | | Subcellular localization | FBXO41 is **cytoplasmic**, excluded from nucleus, with a strong **centrosomal/pericentriolar/centriole** pool in neurons | Mouse knockout / cell biology | Mouse neurons | Colocalizes with **pericentrin**; endogenous FBXO41 recovered in centrosome-enriched fraction | (king2019fbxo41promotesdisassembly pages 2-3, mukherjee2015lossofthe pages 4-4) | | Cell-type/tissue expression | FBXO41 is **neuron-enriched/CNS-selective** rather than broadly glial; expression rises during brain development and is abundant postnatally in cerebellum | Expression profiling | Mouse; human inference from genetics | Detectable from **E10** in mouse; not expressed in astrocytes or oligodendrocytes in cited mouse studies | (king2019fbxo41promotesdisassembly pages 2-3, mukherjee2015lossofthe pages 4-4) | | Biological process: neuronal migration | FBXO41 is required for proper **cerebellar granule neuron migration**; loss causes delayed migration and persistence of cells in inappropriate layers | Mouse knockout | Mouse | FBXO41-null mice show residual **external granule layer at P16** and increased cells in molecular layer; severe ataxia-like phenotype | (mukherjee2015functionalanalysisof pages 142-144, king2019fbxo41promotesdisassembly pages 3-5) | | Biological process: axon growth | Cytoplasmic FBXO41 promotes **axon growth** in cerebellar granule neurons; thesis work links this to non-proteolytic ubiquitination | Mouse neuronal culture / in vivo inference | Mouse | Proposed **K63-linked** ubiquitination of NFM stabilizes substrate and promotes axon extension | (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156) | | Biological process: primary cilia disassembly | Centrosomal FBXO41 promotes **neuronal primary cilia disassembly/shortening**; higher centrosomal FBXO41 correlates with shorter cilia | Cell culture overexpression | Mouse primary hippocampal neurons; hTERT-RPE1 cells | Overexpression reduced both **cilia length** and **% ciliated neurons**; infected at **DIV1→DIV15** or **DIV13→DIV21** with similar effect | (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 3-5, king2019fbxo41promotesdisassembly pages 2-3) | | Pathway impact: Sonic Hedgehog | By altering cilia structure, FBXO41 perturbs **Sonic hedgehog (Shh) signaling**, a canonical cilium-dependent pathway | Cell culture functional assay | Mouse neurons / hTERT-RPE1 cells | Cilia-disassembly phenotype depends on centrosomal targeting and SCF assembly competence | (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) | | Mechanistic modifiers of cilia phenotype | FBXO41-dependent cilia disassembly requires **actin-cytoskeleton rearrangement**; **Aurora A kinase** requirement is seen in mitotic but not post-mitotic cells | Cell biology / pharmacology | Mouse neurons; hTERT-RPE1 cells | **Cytochalasin D** and Aurora A pathway manipulation rescue/prevent shortening in the relevant contexts; **PDBU** recruits overexpressed FBXO41 to centrioles | (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) | | Known/putative partners and substrates | Reported partners/substrates include **SKP1**, **CUL1**, proposed **CUL7**, **DISC1**, possible **NDEL1**, and proposed substrate **NFM** | Biochemical interaction / mouse functional study | Mouse | Direct ubiquitination substrate identification remains limited; strongest replicated partners are SCF components SKP1/CUL1 | (mukherjee2015functionalanalysisof pages 142-144, king2019fbxo41promotesdisassembly pages 2-3, mukherjee2015functionalanalysisof pages 153-156) | | Human rare-disease genetics | A **homozygous c.950G>A (p.Arg317Gln)** FBXO41 variant segregated in an affected family and was absent in controls, supporting possible disease relevance but not definitive causality | Human genetic | Human | Variant absent from **400 control chromosomes**; predicted damaging by **PolyPhen2 ~0.99**, **MutationTaster ~0.99**, **GERP++ 5.17**; **SIFT 0.15** reported tolerated | (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) | | Phenotype association from animal model | FBXO41 loss causes **early mortality, severe ataxia-like gait, cerebellar migration defects, and neurodegeneration** | Mouse knockout | Mouse | Phenotypes reported around **P12–P30**, with strong motor abnormalities at **P16/P30** | (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156) | | Curated disease associations | Disease databases link FBXO41 to **cerebellar ataxia/dysequilibrium/dystonia-related terms**, largely traceable to literature around cerebellar phenotypes rather than established therapeutic targeting | Database curation / literature aggregation | Human | Open Targets evidence scores are modest; example diseases include generalized dystonia and infantile-onset autosomal recessive nonprogressive cerebellar ataxia | (OpenTargets Search: -FBXO41) | | 2024 epigenetic development | In **22q11.2 deletion syndrome**, **FBXO41 showed 14 significant DMPs** and an **exon 2 DMR hypermethylated** in patients vs controls, placing FBXO41 among replicated episignature genes | Human epigenetics | Human blood in 22q11.2DS cohort | Comparison used **14 patients vs 14 controls**; 15 genes overlapped prior episignature, including FBXO41; enrichment p-value for replicated genes **1.12e-6** | (jiao2024epigeneticfactorsin pages 7-10, jiao2024epigeneticfactorsin pages 10-13) | | 2024 cancer/biomarker signal | FBXO41 appears in some recent pan-gene or cancer bioinformatic analyses, but evidence is **indirect and not functionally validated** for FBXO41 itself | Bioinformatic association | Human cancer datasets | In KIRC-related panel analyses, high FBXO41 expression associated with worse OS in univariate analysis, but **not an independent predictor**; no FBXO41-specific HR given in excerpt | (yang2025fboxproteinfbxo21 pages 4-5) | | Evidence gaps / current understanding | No definitive catalytic activity, no validated small-molecule targeting, and no firmly established human substrate repertoire are currently available; best-supported role is as a **neuronal ubiquitin-ligase adaptor regulating centrosome/cilia and cerebellar development** | Synthesis of available evidence | Human with strong support from mouse/cell models | Strongest mechanistic evidence predates 2023; 2023–2024 updates are mainly epigenetic or bioinformatic rather than new core biochemistry | (king2019fbxo41promotesdisassembly pages 1-2, mukherjee2015functionalanalysisof pages 142-144, king2019fbxo41promotesdisassembly pages 2-3, jiao2024epigeneticfactorsin pages 10-13) | *Table: This table summarizes verified identity, domain architecture, molecular function, localization, biological roles, partners, and disease/epigenetic associations for human FBXO41 (UniProt Q8TF61). It highlights where evidence is strongest, especially mouse and cell-based studies, and where recent human findings remain associative rather than mechanistically definitive.* ### 9) Key references (with URLs and dates) * King CR et al. **“Fbxo41 Promotes Disassembly of Neuronal Primary Cilia.”** *Scientific Reports* (2019). Published Jun 2019. https://doi.org/10.1038/s41598-019-44589-2 (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) * Mukherjee C et al. **“Loss of the Neuron-Specific F-Box Protein FBXO41 Models an Ataxia-Like Phenotype in Mice with Neuronal Migration Defects and Degeneration in the Cerebellum.”** *Journal of Neuroscience* (2015). Published Jun 2015. https://doi.org/10.1523/jneurosci.2133-14.2015 (mukherjee2015lossofthe pages 4-4) * Gregianin E. **“Identification and characterisation of novel genes in motor neuron disorders.”** (2014). (URL not available in retrieved metadata.) (gregianin2014identificationandcharacterisationa pages 80-83) * Jiao C et al. **“Epigenetic factors in the 22q11.2 deletion syndrome in relation to stress and schizophrenia.”** *medRxiv* preprint. Posted **June 24, 2024**. https://doi.org/10.1101/2024.06.23.24309352 (jiao2024epigeneticfactorsin pages 7-10, jiao2024epigeneticfactorsin pages 10-13) * Open Targets Platform: FBXO41 disease associations (accessed via tool). https://platform.opentargets.org/ (OpenTargets Search: -FBXO41) References 1. (gregianin2014identificationandcharacterisationa pages 80-83): E Gregianin. Identification and characterisation of novel genes in motor neuron disorders. Unknown journal, 2014. 2. (gregianin2014identificationandcharacterisation pages 80-83): E Gregianin. Identification and characterisation of novel genes in motor neuron disorders. Unknown journal, 2014. 3. (king2019fbxo41promotesdisassembly pages 2-3): Cillian R. King, Ana R. A. A. Quadros, Anaël Chazeau, Ingrid Saarloos, Anne Jolien van der Graaf, Matthijs Verhage, and Ruud F. Toonen. Fbxo41 promotes disassembly of neuronal primary cilia. Scientific Reports, Jun 2019. URL: https://doi.org/10.1038/s41598-019-44589-2, doi:10.1038/s41598-019-44589-2. This article has 18 citations and is from a peer-reviewed journal. 4. (mukherjee2015functionalanalysisof pages 142-144): Chaitali Mukherjee. Functional analysis of the cns-specific f-box protein fbxo41 in cerebellar development. Unknown journal, 2015. URL: https://doi.org/10.53846/goediss-5309, doi:10.53846/goediss-5309. 5. (mukherjee2015functionalanalysisof pages 153-156): Chaitali Mukherjee. Functional analysis of the cns-specific f-box protein fbxo41 in cerebellar development. Unknown journal, 2015. URL: https://doi.org/10.53846/goediss-5309, doi:10.53846/goediss-5309. 6. (king2019fbxo41promotesdisassembly pages 1-2): Cillian R. King, Ana R. A. A. Quadros, Anaël Chazeau, Ingrid Saarloos, Anne Jolien van der Graaf, Matthijs Verhage, and Ruud F. Toonen. Fbxo41 promotes disassembly of neuronal primary cilia. Scientific Reports, Jun 2019. URL: https://doi.org/10.1038/s41598-019-44589-2, doi:10.1038/s41598-019-44589-2. This article has 18 citations and is from a peer-reviewed journal. 7. (mukherjee2015lossofthe pages 4-4): Chaitali Mukherjee, Anna Hołubowska, Nicola Schwedhelm-Domeyer, M. Mitkovski, Shih-Ju Lee, Madhuvanthi Kannan, Annika Matz, Mayur Vadhvani, and Judith Stegmüller. Loss of the neuron-specific f-box protein fbxo41 models an ataxia-like phenotype in mice with neuronal migration defects and degeneration in the cerebellum. The Journal of Neuroscience, 35:8701-8717, Jun 2015. URL: https://doi.org/10.1523/jneurosci.2133-14.2015, doi:10.1523/jneurosci.2133-14.2015. This article has 20 citations. 8. (king2019fbxo41promotesdisassembly pages 3-5): Cillian R. King, Ana R. A. A. Quadros, Anaël Chazeau, Ingrid Saarloos, Anne Jolien van der Graaf, Matthijs Verhage, and Ruud F. Toonen. Fbxo41 promotes disassembly of neuronal primary cilia. Scientific Reports, Jun 2019. URL: https://doi.org/10.1038/s41598-019-44589-2, doi:10.1038/s41598-019-44589-2. This article has 18 citations and is from a peer-reviewed journal. 9. (OpenTargets Search: -FBXO41): Open Targets Query (-FBXO41, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research. 10. (jiao2024epigeneticfactorsin pages 10-13): Chuan Jiao, Fanny Demars, Anton Iftimovici, Qin He, Oussama Kebir, Anushree Tripathi, Hugo Turbé, Caroline Demily, Marie-Odile Krebs, Thérèse M Jay, and Boris Chaumette. Epigenetic factors in the 22q11.2 deletion syndrome in relation to stress and schizophrenia. MedRxiv, Jun 2024. URL: https://doi.org/10.1101/2024.06.23.24309352, doi:10.1101/2024.06.23.24309352. This article has 0 citations. 11. (jiao2024epigeneticfactorsin pages 7-10): Chuan Jiao, Fanny Demars, Anton Iftimovici, Qin He, Oussama Kebir, Anushree Tripathi, Hugo Turbé, Caroline Demily, Marie-Odile Krebs, Thérèse M Jay, and Boris Chaumette. Epigenetic factors in the 22q11.2 deletion syndrome in relation to stress and schizophrenia. MedRxiv, Jun 2024. URL: https://doi.org/10.1101/2024.06.23.24309352, doi:10.1101/2024.06.23.24309352. This article has 0 citations. 12. (yang2025fboxproteinfbxo21 pages 4-5): Wuping Yang, Taile Jing, Cunjin Wu, Minghao Lu, Xiaolin Yao, Dan Xia, and Ding Peng. F-box protein fbxo21 overexpression inhibits the proliferation and metastasis of clear cell renal cell carcinoma and is closely related to the creb pathway and tumor immune cell infiltration. Journal of Translational Medicine, Mar 2025. URL: https://doi.org/10.1186/s12967-025-06356-y, doi:10.1186/s12967-025-06356-y. This article has 2 citations and is from a peer-reviewed journal. ## Artifacts - [Edison artifact artifact-00](FBXO41-deep-research-falcon_artifacts/artifact-00.md) ## Citations 1. mukherjee2015lossofthe pages 4-4 2. mukherjee2015functionalanalysisof pages 142-144 3. mukherjee2015functionalanalysisof pages 153-156 4. gregianin2014identificationandcharacterisationa pages 80-83 5. gregianin2014identificationandcharacterisation pages 80-83 6. jiao2024epigeneticfactorsin pages 10-13 7. jiao2024epigeneticfactorsin pages 7-10 8. https://doi.org/10.1038/s41598-019-44589-2 9. https://doi.org/10.1523/jneurosci.2133-14.2015 10. https://doi.org/10.1101/2024.06.23.24309352 11. https://platform.opentargets.org/ 12. https://doi.org/10.1038/s41598-019-44589-2, 13. https://doi.org/10.53846/goediss-5309, 14. https://doi.org/10.1523/jneurosci.2133-14.2015, 15. https://doi.org/10.1101/2024.06.23.24309352, 16. https://doi.org/10.1186/s12967-025-06356-y,