| Area | Key finding | Evidence type | Quantitative data | Implication for FBXW4 function | Source (paper + year + URL) and context citation id |
|---|---|---|---|---|---|
| Protein biochemistry | Human/murine FBXW4 (dactylin) is an F-box/WD40 protein that assembles with core SCF ubiquitin ligase components and COP9 signalosome proteins in an F-box-dependent manner. | FLAG co-IP, mass spectrometry, gel filtration, mutant analysis | Fbxw4 reported to contain an F-box domain and five WD-40 motifs; deletion of the F-box abolished copurification with E3 ligase/COP9 components. | Strongest direct evidence that FBXW4 functions as an SCF-type substrate-recognition subunit rather than an enzyme or transporter. | Lockwood et al., 2013, https://doi.org/10.1371/journal.pone.0063610 (pqac-00000001, pqac-00000002, pqac-00000006) |
| Protein biochemistry | FBXW4 associates with ubiquitinated cellular proteins, and this interaction increases after proteasome inhibition. | IP/Western blot with MG132 treatment | MG132 increased association of Fbxw4 with ubiquitinated proteins; effect required an intact F-box. | Supports a role in ubiquitin-dependent substrate handling/proteolysis, consistent with SCF substrate recruitment. | Lockwood et al., 2013, https://doi.org/10.1371/journal.pone.0063610 (pqac-00000004, pqac-00000006) |
| Protein biochemistry | Cancer-associated truncating/missense alterations affect FBXW4 WD-repeat region; the locus is also reported lost/under-expressed in cancers. | Mutation mapping, cancer genomic/expression analysis | Frameshift E245fs* predicted to remove the last ~2.5 WD motifs; paper also reports frequent loss/under-expression in human cancers. | WD repeats are likely functionally important for substrate recognition; data suggest possible tumor-suppressive relevance, though specific substrates remain unknown. | Lockwood et al., 2013, https://doi.org/10.1371/journal.pone.0063610 (pqac-00000003, pqac-00000004) |
| Developmental genetics | SHFM3-associated duplications at 10q24 commonly include FBXW4 together with nearby genes (e.g., LBX1, BTRC, POLL, DPCD), but the causal mechanism appears more regulatory than simple FBXW4 coding dosage. | Literature synthesis, microarray breakpoint mapping | Reported recurrent duplications cluster around ~440-570 kb; examples include 447 kb, 512 kb, and 514 kb (chr10:102,962,134-103,476,346; hg19). Distal breakpoints often fall within FBXW4 (5' UTR, intron 2, intron 5). | FBXW4 is a consistent positional candidate at the SHFM3 locus, but evidence points to locus-level cis-regulatory disruption/misexpression rather than isolated FBXW4 coding mutation. | Li et al., 2015, https://doi.org/10.3390/microarrays5010002 (pqac-00000015) |
| Developmental genetics | Early SHFM3 mapping identified duplications spanning the human ortholog of mouse dactylin/Fbxw4; expression data in patient lymphoblasts favored misexpression of neighboring genes. | FISH, duplication mapping, expression assays | Largest duplicated segment contained HUG1, TLX1, LBX1, BTRC, POLL, and SHFM3/FBXW4; minimal duplication ~325 kb; previous rearrangement ~500 kb in 7 families. BTRC and SUFU were significantly upregulated in lymphoblastoid cells. | Supports a model in which FBXW4 sits within a pathogenic regulatory interval whose rearrangement perturbs multiple genes involved in limb development. | Lyle et al., 2006, https://doi.org/10.1002/ajmg.a.31247 (pqac-00000016) |
| Developmental genetics | A Chinese SHFM family carried two discontinuous 10q24 duplications, one partially duplicating FBXW4; authors favored altered regulatory architecture over simple gene overexpression. | Array CGH, qPCR, family segregation | Centromeric duplicated block ~247-260 kb; telomeric block ~114-125 kb including DPCD and part of FBXW4. Limb enhancer hs326 mapped to chr10:103,266,649-103,267,972 between the duplicated blocks. | Partial FBXW4 duplication plus enhancer disruption is consistent with cis-regulatory misexpression affecting the locus during limb development. | Dai et al., 2013, https://doi.org/10.1186/1471-2350-14-45 (pqac-00000014) |
| Developmental genetics | Syndromic and nonsyndromic SHFM3/related distal limb deficiency cases show variable 10q24 duplications including the whole FBXW4 gene; phenotype severity does not track cleanly with duplication size. | Array CGH, FISH, qPCR | Six patients had duplications roughly ~500-650 kb; one interval listed as 102,870,153-103,528,589 bp. One patient had triplication (qPCR fold difference ~2) and more severe defects. One unaffected mother showed ~30% somatic mosaicism in blood with qPCR fold difference ~1.25. | Indicates dosage/regulatory complexity at the locus; FBXW4-containing rearrangements can be pathogenic, variably expressive, and modified by mosaicism/triplication. | Dimitrov et al., 2010, https://doi.org/10.1136/jmg.2008.065888 (pqac-00000011, pqac-00000013) |
| Developmental genetics | Recent family WGS further confirmed pathogenic 10q24.32 microduplication spanning FBXW4 with variable expressivity and mosaic transmission. | Whole-genome sequencing, family validation | Microduplication chr10:102,934,495-103,496,555 encompassing BTRC, POLL, FBXW4, and LBX1; mosaic duplication detected in unaffected paternal grandmother. | Reinforces current clinical use of structural variant testing at the FBXW4-containing SHFM3 locus and the importance of mosaicism in counseling. | Akimova et al., 2024, https://doi.org/10.3389/fgene.2023.1303807 (pqac-00000009) |
| Regulatory genomics | Deletion of a conserved AIS-associated enhancer region near Lbx1 in mice dysregulated several genes in the local contact domain, including Fbxw4. | Mouse CRISPR enhancer deletion, RT-qPCR/expression analysis, chromatin contact mapping | AIS-CRM located ~7.8 kb downstream of Lbx1. At E15.5, Fbxw4 mRNA increased to ~1.8-fold versus WT; Poll increased ~1.7-fold; Npm3 outside the TAD showed no change. | Demonstrates that local noncoding regulatory elements can modulate Fbxw4 expression, supporting a broader regulatory-genomic model for the 10q24 neighborhood. | McCallum-Loudeac et al., 2024, https://doi.org/10.1093/hmg/ddae011 (pqac-00000017, pqac-00000018) |
| Regulatory genomics | The LBX1/AIS-CRM contact domain spans multiple neighboring genes, providing a structural explanation for why noncoding perturbations can alter Fbxw4 expression without FBXW4 coding mutation. | Micro-C/contact map figure and staged expression profiling | Long-range contacts extended ~550 kbp downstream from the LBX1-centered region; significant staged effects included E15.5 Fbxw4 upregulation (P < 0.05). | Offers mechanistic support for interpreting SHFM3 and other 10q24 phenotypes as 3D-regulatory neighborhood disorders that include FBXW4 among the affected targets. | McCallum-Loudeac et al., 2024, https://doi.org/10.1093/hmg/ddae011 (pqac-00000018, pqac-00000019, pqac-00000020) |


*Table: This table consolidates the main biochemical, developmental-genetic, and regulatory-genomic evidence relevant to human FBXW4. It is useful for separating what is directly shown for the FBXW4 protein from what is inferred from 10q24 structural variation and enhancer perturbation studies.*