FBXO31

Summary

FBXO31 (F-box protein 31, HGNC:16510) is a protein-coding gene on chromosome 16q24.2, encoding F-box only protein 31 (Q5XUX0). Substrate-recognition component of the SCF(FBXO31) protein ligase complex, which specifically mediates the ubiquitination of proteins amidated at their C-terminus in response to oxidative stress, leading to their degradation by the proteasome.

This gene is a member of the F-box family. Members are classified into three classes according to the substrate interaction domain, FBW for WD40 repeats, FBL for leucing-rich repeats, and FBXO for other domains. This protein, classified into the last category because of the lack of a recognizable substrate binding domain, has been proposed to be a component of the SCF ubiquitination complex. It is thought to bind and recruit substrate for ubiquitination and degradation. This protein may have a role in regulating the cell cycle as well as dendrite growth and neuronal migration. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 79791 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebral palsy (Strong, GenCC) — +3 more curated relationships
• Clinical variants (ClinVar): 136 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_024735

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16510
Approved symbol	FBXO31
Name	F-box protein 31
Location	16q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FBX14, FBXO14, Fbx31, MGC15419
Ensembl gene	ENSG00000103264
Ensembl biotype	protein_coding
OMIM	609102
Entrez	79791

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000311635, ENST00000561664, ENST00000563956, ENST00000565593, ENST00000567622, ENST00000569412, ENST00000618298, ENST00000636077, ENST00000866615, ENST00000866616, ENST00000866617, ENST00000930533, ENST00000930534, ENST00000971306

RefSeq mRNA: 2 — MANE Select: NM_024735 NM_001282683, NM_024735

CCDS: CCDS32501, CCDS73922

Canonical transcript exons

ENST00000311635 — 9 exons

Exon	Start	End
ENSE00002601598	87383405	87383776
ENSE00003534156	87360295	87360366
ENSE00003633389	87347174	87347250
ENSE00003798115	87343598	87343765
ENSE00003988756	87326987	87331510
ENSE00003988757	87336155	87336264
ENSE00003988758	87342877	87342951
ENSE00003988759	87335304	87335457
ENSE00003988760	87333886	87334286

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 97.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.2998 / max 256.3678, expressed in 1813 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158468	22.1814	1807
158470	1.4411	717
158467	0.3271	155
158469	0.2159	89
158466	0.0917	41
158465	0.0426	12

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	97.43	gold quality
cerebellar cortex	UBERON:0002129	97.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.15	gold quality
left testis	UBERON:0004533	96.84	gold quality
right testis	UBERON:0004534	96.84	gold quality
cerebellum	UBERON:0002037	96.80	gold quality
cerebellar vermis	UBERON:0004720	96.30	gold quality
gastrocnemius	UBERON:0001388	96.04	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.71	gold quality
muscle of leg	UBERON:0001383	95.55	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.75	gold quality
adenohypophysis	UBERON:0002196	94.53	gold quality
popliteal artery	UBERON:0002250	94.40	gold quality
tibial artery	UBERON:0007610	94.40	gold quality
body of uterus	UBERON:0009853	93.96	gold quality
testis	UBERON:0000473	93.93	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.91	gold quality
omental fat pad	UBERON:0010414	93.89	gold quality
peritoneum	UBERON:0002358	93.84	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.82	gold quality
skin of leg	UBERON:0001511	93.78	gold quality
lower esophagus	UBERON:0013473	93.78	gold quality
mucosa of stomach	UBERON:0001199	93.57	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.47	gold quality
pituitary gland	UBERON:0000007	93.40	gold quality
apex of heart	UBERON:0002098	93.33	gold quality
aorta	UBERON:0000947	93.20	gold quality
endocervix	UBERON:0000458	93.19	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.05	gold quality
tibial nerve	UBERON:0001323	93.03	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

99 targeting FBXO31, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6745	99.74	65.33	1321

Literature-anchored findings (GeneRIF, showing 30)

• Loss of FBXO31 is associated with breast cancer (PMID:16357137)
• ectopic expression of FBXO31 acts through a proteasome-directed pathway to mediate the degradation of cyclin D1, an important regulator of progression from G1 to S phase, resulting in arrest in G1 (PMID:19412162)
• CGH array indicated that cases having cyclin D1 with increased copy number were significantly associated with elevated FBXO31 expression levels (P<0.05). FBXO31 could be a novel and robust prognostic marker for ESCC. (PMID:21537837)
• The Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane recruitment in response to EGF. (PMID:22632973)
• ascribe a role for FBXO31 in dendrite growth and neuronal migration in the developing cerebellar cortex. Taken together, we uncovered the centrosomal E3 ligase FBXO31-SCF as a novel regulator of neuronal development (PMID:23469015)
• Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability. (PMID:24623383)
• FBXO31 interacts with Cdt1 and regulates the degradation of Cdt1 in G2 phase. (PMID:24828503)
• uncover a new mechanism of deactivation of MKK6-p38 and substantiate a novel regulatory role of FBXO31 in stress response (PMID:24936062)
• Expression of FBXO31 inhibited xenograft tumor growth in mice. miR-20a and miR-17 mimics inhibited, whereas the inhibitor of miR-20a and miR-17 increased, the expression of FBXO31, respectively. miR-20a and miR-17 directly bind to the 3’-UTR of FBXO31. (PMID:25115392)
• FBXO31-mediated loss of MDM2 leads to elevated levels of p53, resulting in growth arrest. In cells depleted of FBXO31, MDM2 is not degraded and p53 levels do not increase following genotoxic stress (PMID:26124108)
• FBXO31 targets and ubiquitylates Slug for proteasomal degradation. However, this mechanism is repressed in breast tumors where miR-93 and miR-106a are overexpressed. Our study further unravels an interesting mechanism whereby Slug drives the expression of miR-93 and miR-106a, thus establishing a positive feedback loop to maintain an invasive phenotype (PMID:28500896)
• in addition to revealing that FBXO31 is an independent prognostic marker for esophageal squamous cell carcinoma , our findings substantiate a novel regulatory role of FBXO31 in tumorigenesis and drug resistance of esophageal squamous cell carcinoma (PMID:28905993)
• Results identified FBXO31 as a novel E3 ubiquitin ligase of Snail1, and its low expression contributes to an aberrant accumulation of Snail1 in gastric cancer. Furthermore, F-box domain of FBXO31 and the phosphorylation of Snail1 are essential for the interaction and degradation. These findings reveal the important function of FBXO31 on the regulation of Snail1 protein level in gastric cancer. (PMID:29117943)
• Findings indicate the substrate specificity of the F-box protein FBXO31 and the mechanism of FBXO31-regulated cyclin D1 protein turnover. (PMID:29279382)
• results reveal how alterations in FBXO31 phosphorylation, mediated by AKT and ATM, underlie physiological regulation of FBXO31 levels in unstressed and genotoxically stressed cells (PMID:29343641)
• Higher mRNA expression levels of FBXO1, FBXO31, SKP2, and FBXO5 were significantly associated with worse prognosis for breast cancer patients. (Review) (PMID:30341246)
• FBXO31 plays a pivotal role in preserving genomic integrity by maintaining low cyclin A levels during the G1 phase for faithful genome duplication and segregation (PMID:31413110)
• F-box protein FBXO31 modulates apoptosis and epithelial-mesenchymal transition of cervical cancer via inactivation of the PI3K/AKT-mediated MDM2/p53 axis. (PMID:32800832)
• Mutations disrupting neuritogenesis genes confer risk for cerebral palsy. (PMID:32989326)
• MicroRNA-210 targets FBXO31 to inhibit tumor progression and regulates the Wnt/beta-catenin signaling pathway and EMT in esophageal squamous cell carcinoma. (PMID:33538099)
• Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome. (PMID:33675180)
• Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis. (PMID:34686346)
• Feedback-regulated transcriptional repression of FBXO31 by c-Myc triggers ovarian cancer tumorigenesis. (PMID:34706096)
• Effects and mechanisms of FBXO31 on Taxol chemoresistance in esophageal squamous cell carcinoma. (PMID:34839191)
• Novel variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability in Iranian consanguineous families. (PMID:35019165)
• FBXO31 suppresses lipogenesis and tumor progression in glioma by promoting ubiquitination and degradation of CD147. (PMID:35940557)
• FBXO31 sensitizes cancer stem cells-like cells to cisplatin by promoting ferroptosis and facilitating proteasomal degradation of GPX4 in cholangiocarcinoma. (PMID:36269678)
• LincRNA ZNF529-AS1 inhibits hepatocellular carcinoma via FBXO31 and predicts the prognosis of hepatocellular carcinoma patients. (PMID:36803542)
• Aberrantly High FBXO31 Impairs Oocyte Quality in Premature Ovarian Insufficiency. (PMID:37611899)
• FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation. (PMID:38216561)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo31	ENSDARG00000062195
mus_musculus	Fbxo31	ENSMUSG00000052934
rattus_norvegicus	Fbxo31	ENSRNOG00000042274

Paralogs (1): FBXO39 (ENSG00000177294)

Protein

Protein identifiers

F-box only protein 31 — Q5XUX0 (reviewed: Q5XUX0)

All UniProt accessions (4): Q5XUX0, A0A0C4DGU8, A0A1B0GV77, H3BQG7

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF(FBXO31) protein ligase complex, which specifically mediates the ubiquitination of proteins amidated at their C-terminus in response to oxidative stress, leading to their degradation by the proteasome. FBXO31 specifically recognizes and binds C-terminal peptides bearing an amide: C-terminal amidation in response to oxidative stress takes place following protein fragmentation. The SCF(FBXO31) also plays a role in G1 arrest following DNA damage by mediating ubiquitination of phosphorylated cyclin-D1 (CCND1), promoting its degradation by the proteasome, resulting in G1 arrest. The SCF(FBXO31) complex is however not a major regulator of CCND1 stability during the G1/S transition. In response to genotoxic stress, the SCF(FBXO31) complex directs ubiquitination and degradation of phosphorylated MDM2, thereby promoting p53/TP53-mediated DNA damage response. SCF(FBXO31) complex is required for genomic integrity by catalyzing ubiquitination and degradation of cyclin-A (CCNA1 and/or CCNA2) during the G1 phase. In response to genotoxic stress, the SCF(FBXO31) complex directs ubiquitination and degradation of phosphorylated FBXO46 and MAP2K6. SCF(FBXO31) complex promotes ubiquitination and degradation of CDT1 during the G2 phase to prevent re-replication. The SCF(FBXO31) complex also mediates ubiquitination and degradation of DUSP6, OGT and PARD6A.

Subunit / interactions. Part of a SCF (SKP1-cullin-F-box) protein ligase complex SCF(FBXO31) composed of CUL1, SKP1, RBX1 and FBXO31. Interacts (when phosphorylated at Ser-33) with CDC20, promoting ubiquitination by the APC/C complex.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Highly expressed in brain. Expressed at moderate levels in most tissues, except bone marrow.

Post-translational modifications. Phosphorylation at Ser-278 by ATM following gamma-irradiation results in its stabilization. Phosphorylation at Thr-419 and Ser-480 in absence of stress promotes its ubiquitination and degradation by the SCF(FBXO46) complex. Phosphorylation at Ser-33 by AKT1 promotes association with CDC20 and ubiquitination by the APC/C complex. Ubiquitinated by the SCF(FBXO46) complex in absence of stress, promoting its degradation. Ubiquitinated by the APC/C complex following phosphorylation at Ser-33, leading to its degradation by the proteasome.

Disease relevance. Intellectual developmental disorder, autosomal recessive 45 (MRT45) [MIM:615979] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT45 manifestations include mild to moderate intellectual disability and dysmorphic features, including coarse facies, broad nasal bridge, fleshy nares, and thick, prominent lips. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Zinc-binding is required for the structure of the protein and facilitate folding. The destruction box (D box) acts as a recognition signal for CDC20 for degradation by the APC/C complex. The DDL motif is required for the interation with cyclin-A (CCNA1 and/or CCNA2).

Induction. By DNA damage. Increases after UV irradiation, X-ray irradiation, oxidative stress (H(2)O(2)) or addition of the chemotherapeutic DNA-damaging agents etoposide, adriamycin, cisplatin or fluorouracil.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the FBXO31 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5XUX0-1	1	yes
Q5XUX0-2	2

RefSeq proteins (2): NP_001269612, NP_079011* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR045048	FBXO31/39	Family

Pfam: PF12014, PF12937

UniProt features (82 total): strand 21, mutagenesis site 18, helix 17, modified residue 6, binding site 4, sequence conflict 3, turn 3, region of interest 2, short sequence motif 2, compositionally biased region 2, chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5VZT	X-RAY DIFFRACTION	2.7
5VZU	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5XUX0-F1	84.61	0.75

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 230; 236; 206; 214

Post-translational modifications (6): 33, 33, 37, 278, 419, 480

Mutagenesis-validated functional residues (18):

Position	Phenotype
33	abolished phosphorylation by akt1.
64–67	abolished ubiquitination and degradation by the apc/c complex.
206	impaired folding, inducing the formation of insoluble aggregates.
214	impaired folding, inducing the formation of insoluble aggregates.
230	impaired folding, inducing the formation of insoluble aggregates.
236	impaired folding, inducing the formation of insoluble aggregates.
278	fails to accumulate following gamma-irradiation.
297–299	abolished interaction with cyclin-a.
309	abolished ability to promote ubiquitination of amidated proteins.
311	does not affect ability to promote ubiquitination of ccnd1.
312	decreased ability to promote ubiquitination of ccnd1.
330	decreased ability to promote ubiquitination of ccnd1.
337	abolished ability to promote ubiquitination of amidated proteins.
343	abolished ability to promote ubiquitination of amidated proteins.
400	no effect following gamma-irradiation.
419	decreased phosphorylation, leading to impair ubiquitination by the scf(fbxo46) complex.
461–464	abolished interaction with fbxo46, preventing ubiquitination and degradation by the scf(fbxo46) complex.
480	decreased phosphorylation, leading to impair ubiquitination by the scf(fbxo46) complex.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 239 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_ANAPHASE_PROMOTING_COMPLEX_DEPENDENT_CATABOLIC_PROCESS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE_G1_S_PHASE_TRANSITION, GOCC_CENTROSOME, GOBP_CELL_CYCLE_G1_S_PHASE_TRANSITION, GOBP_NEGATIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GOBP_DNA_DAMAGE_RESPONSE

GO Biological Process (11): DNA damage response (GO:0006974), protein ubiquitination (GO:0016567), anaphase-promoting complex-dependent catabolic process (GO:0031145), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), mitotic G1 DNA damage checkpoint signaling (GO:0031571), cellular response to oxidative stress (GO:0034599), signal transduction in response to DNA damage (GO:0042770), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), DNA damage response, signal transduction by p53 class mediator (GO:0030330), p38MAPK cascade (GO:0038066), negative regulation of signal transduction by p53 class mediator (GO:1901797)

GO Molecular Function (3): cyclin binding (GO:0030332), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (6): cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), neuronal cell body (GO:0043025), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteasome-mediated ubiquitin-dependent protein catabolic process	2
signal transduction by p53 class mediator	2
cellular anatomical structure	2
cellular response to stress	1
protein modification by small protein conjugation	1
mitotic G1 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G1/S transition checkpoint signaling	1
response to oxidative stress	1
cellular response to chemical stress	1
DNA damage response	1
intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
signal transduction in response to DNA damage	1
MAPK cascade	1
regulation of signal transduction by p53 class mediator	1
negative regulation of intracellular signal transduction	1
protein binding	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
cullin-RING ubiquitin ligase complex	1
somatodendritic compartment	1
cell body	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

498 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO31	SKP1	P34991	654
FBXO31	CUL1	Q13616	634
FBXO31	CCND1	P24385	491
FBXO31	FBXO5	Q9UKT4	473
FBXO31	BRAF	P15056	469
FBXO31	ATM	Q13315	420
FBXO31	FBXO34	Q9NWN3	405
FBXO31	FBXO4	Q9UKT5	392
FBXO31	TMEM26	Q6ZUK4	386
FBXO31	FBXO42	Q6P3S6	355
FBXO31	FBXW11	Q9UKB1	350
FBXO31	FBXO22	Q8NEZ5	348
FBXO31	CCNF	P41002	344
FBXO31	ASB14	A6NK59	329
FBXO31	C16orf95	Q9H693	325

IntAct

24 interactions, top by confidence:

A	B	Type	Score
PRPS1	PRPSAP2	psi-mi:“MI:0914”(association)	0.840
FBXO31	SKP1	psi-mi:“MI:0915”(physical association)	0.670
FAM98A	HERC2	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
CUL1	FBXO21	psi-mi:“MI:0914”(association)	0.600
FBXO31	CCND1	psi-mi:“MI:0914”(association)	0.580
CCND1	FBXO31	psi-mi:“MI:0915”(physical association)	0.580
FBXO31	ATM	psi-mi:“MI:0217”(phosphorylation reaction)	0.540
FBXO31	ATM	psi-mi:“MI:0915”(physical association)	0.540
MYH6	ELOC	psi-mi:“MI:0914”(association)	0.350
Kctd5		psi-mi:“MI:0914”(association)	0.350
CEP170P1	PCYT1A	psi-mi:“MI:0914”(association)	0.350
Skp1	XPO1	psi-mi:“MI:0914”(association)	0.350
FBXO31	CCNQ	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
STYX	BANF1	psi-mi:“MI:0914”(association)	0.350
SKP1	BHLHE40	psi-mi:“MI:0914”(association)	0.350
RBX1	OBSL1	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350
SKP1	NDUFAB1	psi-mi:“MI:0914”(association)	0.350

BioGRID (112): FBXO31 (Affinity Capture-Western), CDT1 (Affinity Capture-Western), CCND1 (Reconstituted Complex), CDT1 (Reconstituted Complex), CDT1 (Biochemical Activity), STX3 (Affinity Capture-MS), CUL1 (Affinity Capture-MS), PDLIM1 (Affinity Capture-MS), MRPS27 (Affinity Capture-MS), EFR3A (Affinity Capture-MS), EDRF1 (Affinity Capture-MS), FBXO31 (Affinity Capture-MS), FBXO31 (Affinity Capture-MS), FBXO31 (Affinity Capture-MS), QSER1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMQ9, A2BD94, A2RRT3, A8WHR0, B2RYN2, D3ZKV9, O36371, O43147, P03177, P41958, Q0D2D2, Q1HVD1, Q1LVQ2, Q2NKQ1, Q3KSQ2, Q3TQF0, Q4R8E0, Q4V8Z3, Q5EA86, Q5R8D5, Q5U228, Q5U430, Q5XUX0, Q68FS7, Q6INH1, Q6NU22, Q6NU51, Q6ZN28, Q6ZUJ8, Q7ZUL9, Q80TM9, Q80U12, Q84WW1, Q8AXQ3, Q8BMQ2, Q8BPQ7, Q8IXX5, Q8SX86, Q9BQI3, Q9D5Z5

Diamond homologs: A2BD94, A2RRT3, B2RYN2, Q0D2D2, Q3TQF0, Q5XUX0, Q9ZUB8, Q9ZUB9

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
ATM	up-regulates	FBXO31	phosphorylation
AKT1	“down-regulates quantity by destabilization”	FBXO31	phosphorylation
CDH1	“down-regulates quantity by destabilization”	FBXO31	binding
CDC20	“down-regulates quantity by destabilization”	FBXO31	binding
FBXO31	“down-regulates quantity by destabilization”	CCND1	binding
FBXO31	“down-regulates quantity by destabilization”	MDM2	binding
FBXO31	“up-regulates activity”	“Cullin 7-RBX1-Skp1”	binding
FBXO31	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neddylation	7	18.4×	6e-06
Antigen processing: Ubiquitination & Proteasome degradation	6	12.4×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	6	9.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

136 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	86
Likely benign	22
Benign	5

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
155905	NM_024735.5(FBXO31):c.847_852delinsA (p.Cys283fs)	Pathogenic
813309	GRCh37/hg19 16q24.1-24.2(chr16:84872102-87678641)	Pathogenic
3376842	NM_024735.5(FBXO31):c.842+1G>A	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3537 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:87331410:A:G	W500R	1.000
16:87331410:A:T	W500R	1.000
16:87331474:G:C	F478L	1.000
16:87331474:G:T	F478L	1.000
16:87331476:A:G	F478L	1.000
16:87334275:G:C	N336K	1.000
16:87334275:G:T	N336K	1.000
16:87334282:T:A	D334V	1.000
16:87334282:T:C	D334G	1.000
16:87334282:T:G	D334A	1.000
16:87334285:C:A	G333V	1.000
16:87334285:C:T	G333D	1.000
16:87334286:C:A	G333C	1.000
16:87334286:C:G	G333R	1.000
16:87335310:C:A	K330N	1.000
16:87335310:C:G	K330N	1.000
16:87335364:G:C	H312Q	1.000
16:87335364:G:T	H312Q	1.000
16:87335366:G:C	H312D	1.000
16:87335381:C:G	G307R	1.000
16:87335444:A:C	Y286D	1.000
16:87335449:A:G	L284P	1.000
16:87336173:A:T	I275N	1.000
16:87336175:G:C	F274L	1.000
16:87336175:G:T	F274L	1.000
16:87336176:A:G	F274S	1.000
16:87336177:A:G	F274L	1.000
16:87336181:C:A	M272I	1.000
16:87336181:C:G	M272I	1.000
16:87336181:C:T	M272I	1.000

dbSNP variants (sampled 300 via entrez): RS1000071725 (16:87376057 C>T), RS1000139114 (16:87340126 T>C), RS1000147932 (16:87365348 A>T), RS1000171798 (16:87372978 A>C), RS1000217271 (16:87344260 C>A,T), RS1000235771 (16:87382689 T>A,C), RS1000247193 (16:87382978 C>A,T), RS1000272603 (16:87353619 C>A,T), RS1000293156 (16:87349730 G>A,T), RS1000333602 (16:87375949 G>A), RS1000355520 (16:87391323 A>C,G), RS1000411960 (16:87344001 G>A), RS1000414042 (16:87373852 C>T), RS1000447740 (16:87378394 G>A,C), RS1000457575 (16:87336008 G>A)

Disease associations

OMIM: gene MIM:609102 | disease phenotypes: MIM:615979, MIM:265380

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebral palsy	Strong	Autosomal dominant
intellectual disability, autosomal recessive	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive
intellectual disability, autosomal recessive 45	Limited	Autosomal recessive

Mondo (7): intellectual disability, autosomal recessive 45 (MONDO:0014430), spastic cerebral palsy (MONDO:0000396), thyroid ectopia (MONDO:0019854), alveolar capillary dysplasia with misalignment of pulmonary veins (MONDO:0009934), cerebral palsy (MONDO:0006497), intellectual disability, autosomal recessive (MONDO:0100597), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (3): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Thyroid ectopia (Orphanet:95712), Congenital alveolar capillary dysplasia (Orphanet:210122)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
C536590	Alveolar capillary dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, decreases methylation, increases abundance	2
Benzo(a)pyrene	decreases expression	2
Valproic Acid	increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	decreases methylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	decreases expression	1
Lead	affects methylation	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	increases expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Quercetin	decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Vitamin E	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Gold Compounds	increases methylation	1
Metals, Heavy	decreases methylation, increases abundance	1

Clinical trials (associated diseases)

368 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00732537	PHASE4	COMPLETED	Inhaled Nitric Oxide by Oxygen Hood in Neonates
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02839785	PHASE3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	PHASE3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A