FBXO21

Summary

FBXO21 (F-box protein 21, HGNC:13592) is a protein-coding gene on chromosome 12q24.22, encoding F-box only protein 21 (O94952). Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. Alternative splicing of this gene generates 2 transcript variants.

Source: NCBI Gene 23014 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 75 total — 2 pathogenic
• MANE Select transcript: NM_015002

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13592
Approved symbol	FBXO21
Name	F-box protein 21
Location	12q24.22
Locus type	gene with protein product
Status	Approved
Aliases	FBX21, KIAA0875
Ensembl gene	ENSG00000135108
Ensembl biotype	protein_coding
OMIM	609095
Entrez	23014

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000330622, ENST00000547806, ENST00000548840, ENST00000549689, ENST00000550180, ENST00000551458, ENST00000622495, ENST00000880236, ENST00000923449, ENST00000923450, ENST00000948437, ENST00000948438, ENST00000948439

RefSeq mRNA: 2 — MANE Select: NM_015002 NM_015002, NM_033624

CCDS: CCDS44989, CCDS9184

Canonical transcript exons

ENST00000622495 — 12 exons

Exon	Start	End
ENSE00000938009	117174651	117174797
ENSE00000938011	117172471	117172607
ENSE00000938012	117166898	117167077
ENSE00000938013	117165485	117165617
ENSE00001330331	117157873	117158063
ENSE00002338855	117190218	117190470
ENSE00003583138	117155791	117155948
ENSE00003628582	117174205	117174341
ENSE00003641065	117177520	117177641
ENSE00003668292	117186477	117186571
ENSE00003721219	117141991	117146277
ENSE00003731294	117189227	117189362

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.5918 / max 257.0062, expressed in 1817 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133497	35.4565	1817
133498	0.1353	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.57	gold quality
caput epididymis	UBERON:0004358	99.35	gold quality
cauda epididymis	UBERON:0004360	98.10	gold quality
right uterine tube	UBERON:0001302	97.59	gold quality
adult organism	UBERON:0007023	97.36	gold quality
metanephric glomerulus	UBERON:0004736	96.58	gold quality
renal glomerulus	UBERON:0000074	96.35	gold quality
renal medulla	UBERON:0000362	96.30	gold quality
postcentral gyrus	UBERON:0002581	96.22	gold quality
kidney epithelium	UBERON:0004819	95.80	gold quality
cerebellar vermis	UBERON:0004720	95.78	gold quality
parietal lobe	UBERON:0001872	95.50	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.33	gold quality
entorhinal cortex	UBERON:0002728	95.09	gold quality
ventricular zone	UBERON:0003053	94.94	gold quality
adrenal tissue	UBERON:0018303	94.93	gold quality
paraflocculus	UBERON:0005351	94.91	gold quality
nephron tubule	UBERON:0001231	94.72	gold quality
ganglionic eminence	UBERON:0004023	94.49	gold quality
superior frontal gyrus	UBERON:0002661	94.46	gold quality
left ovary	UBERON:0002119	94.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.25	gold quality
germinal epithelium of ovary	UBERON:0001304	94.23	gold quality
cortical plate	UBERON:0005343	94.21	gold quality
ovary	UBERON:0000992	94.18	gold quality
cranial nerve II	UBERON:0000941	94.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.14	gold quality
Brodmann (1909) area 10	UBERON:0013541	94.10	gold quality
endothelial cell	CL:0000115	94.07	gold quality
biceps brachii	UBERON:0001507	93.97	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	87.06
E-ANND-3	yes	12.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting FBXO21, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-380-3P	99.89	70.18	1978

Literature-anchored findings (GeneRIF, showing 6)

• The results suggest that EID1 is a bona fide substrate of FBXO21 and that the control of EID1 abundance by SCF(FBXO)(21) might affect the transcriptional repression activity of EID1. (PMID:26085330)
• Ser291-phosphorylated form of the multifunctional protein and stem cell marker, CD44, inhibits FBXO21-directed degradation of P-gp. (PMID:26299618)
• SCF(FBXO21) polyubiquitylates EID1 both in vitro and in vivo and is required for the efficient degradation of EID1 in both cycling and quiescent cells. (PMID:26631746)
• JUNB-FBXO21-ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy. (PMID:33450132)
• circRNA-MSR regulates the expression of FBXO21 to inhibit chondrocyte autophagy by targeting miR-761 in osteoarthritis. (PMID:36278814)
• FBXO21 mediated degradation of p85alpha regulates proliferation and survival of acute myeloid leukemia. (PMID:37689825)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo21	ENSDARG00000076611
mus_musculus	Fbxo21	ENSMUSG00000032898
rattus_norvegicus	Fbxo21	ENSRNOG00000001129

Protein

Protein identifiers

F-box only protein 21 — O94952 (reviewed: O94952)

All UniProt accessions (3): O94952, H0YHF6, H0YIE9

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

Subunit / interactions. Directly interacts with SKP1 and CUL1.

Miscellaneous. May be due to a competing acceptor splice site.

Isoforms (2)

UniProt ID	Names	Canonical?
O94952-2	1	yes
O94952-1	2

RefSeq proteins (2): NP_055817, NP_296373 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR011722	Hemimethylated_DNA-bd_dom	Domain
IPR032698	SirB1_N	Domain
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR036623	Hemimethylated_DNA-bd_sf	Homologous_superfamily

Pfam: PF08755, PF12937, PF13369

UniProt features (4 total): chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94952-F1	85.81	0.57

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: 235 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GCM_MAP4K4, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, WONG_PROTEASOME_GENE_MODULE, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_HEMATOPOIETIC_STEM_CELL_DIFFERENTIATION, ATGTTAA_MIR302C, UEDA_PERIFERAL_CLOCK

GO Biological Process (6): ubiquitin-dependent protein catabolic process (GO:0006511), apoptotic process (GO:0006915), cytokine-mediated signaling pathway (GO:0019221), hematopoietic stem cell differentiation (GO:0060218), hematopoietic stem cell homeostasis (GO:0061484), ERK1 and ERK2 cascade (GO:0070371)

GO Molecular Function (3): DNA binding (GO:0003677), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515)

GO Cellular Component (2): ubiquitin ligase complex (GO:0000151), cytosol (GO:0005829)

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
protein ubiquitination	1
modification-dependent protein catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
hematopoietic progenitor cell differentiation	1
stem cell differentiation	1
homeostasis of number of cells	1
MAPK cascade	1
nucleic acid binding	1
ubiquitin-like protein transferase activity	1
binding	1
intracellular protein-containing complex	1
transferase complex	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

862 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO21	SKP1	P34991	902
FBXO21	CUL1	Q13616	826
FBXO21	SSC4D	Q8WTU2	535
FBXO21	USP31	Q70CQ4	506
FBXO21	MAIP1	Q8WWC4	506
FBXO21	DET1	Q7L5Y6	501
FBXO21	FBXO32	Q969P5	465
FBXO21	FBXO41	Q8TF61	462
FBXO21	USP30	Q70CQ3	459
FBXO21	FBXW8	Q8N3Y1	458
FBXO21	FBLN1	P23142	452
FBXO21	ZMAT5	Q9UDW3	451
FBXO21	EID1	Q9Y6B2	447
FBXO21	STOX2	Q9P2F5	443
FBXO21	GCNA	Q96QF7	429

IntAct

75 interactions, top by confidence:

A	B	Type	Score
FBXO21	SKP1	psi-mi:“MI:0914”(association)	0.770
SKP1	FBXO21	psi-mi:“MI:0915”(physical association)	0.770
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
EID1	FBXO21	psi-mi:“MI:0915”(physical association)	0.650
FBXO21	EID1	psi-mi:“MI:0403”(colocalization)	0.650
EID1	FBXO21	psi-mi:“MI:0914”(association)	0.650
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
CUL1	FBXO21	psi-mi:“MI:0914”(association)	0.600
FBXO21	RBX1	psi-mi:“MI:0914”(association)	0.530
VWCE	ZNF316	psi-mi:“MI:0914”(association)	0.530
CRYAB	CCDC85C	psi-mi:“MI:0914”(association)	0.530
PRKCA	DUSP11	psi-mi:“MI:0914”(association)	0.530
SGSH	FBXO21	psi-mi:“MI:0914”(association)	0.530
GALNS	FBXO21	psi-mi:“MI:0914”(association)	0.530
GALNS	CLGN	psi-mi:“MI:0914”(association)	0.530
IGFBP4	CETN3	psi-mi:“MI:0914”(association)	0.530
KERA	FBXO21	psi-mi:“MI:0914”(association)	0.530
MCEE	CLUH	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
PRTN3	FBXO21	psi-mi:“MI:0914”(association)	0.530

BioGRID (107): FBXO21 (Affinity Capture-RNA), FBXO21 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), EID1 (Affinity Capture-Western), CUL1 (Affinity Capture-Western), RBX1 (Affinity Capture-Western), EID1 (Biochemical Activity), FBXO21 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IMY7, A0A0R4IY06, A0JPF9, A2AP18, A5PJN5, C0IN03, D2KX21, E1BVR9, E9PYK3, F1ND48, O00534, O75038, O94952, O95237, P0C1Q3, P53817, Q1LWG4, Q1LZ50, Q32PY6, Q4R3W5, Q4R6L3, Q5M7X9, Q5R5S1, Q5RJG7, Q5S6T3, Q5T8I9, Q6DC39, Q75WE7, Q7Z5M8, Q7ZU92, Q8BYI6, Q8C0L6, Q8CAE2, Q8CAS9, Q8K3R3, Q8NHH9, Q8SPR7, Q8VDH1, Q90678, Q93V51

Diamond homologs: O94952, P45252, Q5R5S1, Q67Y99, Q87DH6, Q8VDH1, Q9CN81, Q9HYI6, Q9KQ28, Q9PD85, P0A2L9, P0A2M0, P0AGM5, P0AGM6, P57270, Q89AS9, Q8K9W8, Q6D6C5

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
FBXO21	“down-regulates quantity by destabilization”	EID1	binding
FBXO21	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
FBXO21	“down-regulates quantity by destabilization”	ABCB1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 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	5.7×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	61
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2685457	GRCh37/hg19 12q24.21-24.23(chr12:116499832-118681240)x1	Pathogenic
395069	GRCh37/hg19 12q24.21-24.23(chr12:116028864-118791808)x1	Pathogenic

SpliceAI

2250 predictions. Top by Δscore:

Variant	Effect	Δscore
12:117155785:GCTTA:G	donor_loss	1.0000
12:117155786:CTTAC:C	donor_loss	1.0000
12:117155787:TTA:T	donor_loss	1.0000
12:117155788:TA:T	donor_loss	1.0000
12:117155789:A:AC	donor_gain	1.0000
12:117155789:A:AG	donor_loss	1.0000
12:117155790:C:CC	donor_gain	1.0000
12:117155790:C:T	donor_loss	1.0000
12:117155944:CATAC:C	acceptor_gain	1.0000
12:117155945:ATACC:A	acceptor_loss	1.0000
12:117155946:TAC:T	acceptor_gain	1.0000
12:117155946:TACC:T	acceptor_loss	1.0000
12:117155947:ACCTA:A	acceptor_loss	1.0000
12:117155948:CCTAG:C	acceptor_loss	1.0000
12:117155949:C:CA	acceptor_loss	1.0000
12:117155950:T:A	acceptor_loss	1.0000
12:117155953:T:C	acceptor_gain	1.0000
12:117157868:CTCA:C	donor_loss	1.0000
12:117157869:TCA:T	donor_loss	1.0000
12:117157870:CACC:C	donor_loss	1.0000
12:117157871:A:C	donor_loss	1.0000
12:117157872:C:G	donor_loss	1.0000
12:117157872:CCT:C	donor_gain	1.0000
12:117165480:ATTAC:A	donor_loss	1.0000
12:117165481:TTA:T	donor_loss	1.0000
12:117165482:TACC:T	donor_loss	1.0000
12:117165484:C:CG	donor_loss	1.0000
12:117165484:CCTT:C	donor_gain	1.0000
12:117165613:CTTCC:C	acceptor_gain	1.0000
12:117165615:TCCCT:T	acceptor_loss	1.0000

AlphaMissense

4091 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:117146217:A:G	F586S	1.000
12:117146271:A:C	L568W	1.000
12:117146271:A:G	L568S	1.000
12:117155796:G:T	A564D	1.000
12:117155802:T:C	Y562C	1.000
12:117155803:A:G	Y562H	1.000
12:117155818:C:G	D557H	1.000
12:117155826:A:G	L554P	1.000
12:117155829:A:T	V553E	1.000
12:117155836:A:C	Y551D	1.000
12:117155837:G:C	F550L	1.000
12:117155837:G:T	F550L	1.000
12:117155839:A:G	F550L	1.000
12:117155871:A:T	V539D	1.000
12:117155888:C:A	W533C	1.000
12:117155888:C:G	W533C	1.000
12:117155890:A:G	W533R	1.000
12:117155890:A:T	W533R	1.000
12:117155906:G:C	C527W	1.000
12:117155908:A:G	C527R	1.000
12:117155918:C:A	W523C	1.000
12:117155918:C:G	W523C	1.000
12:117155920:A:G	W523R	1.000
12:117155920:A:T	W523R	1.000
12:117155933:A:C	C518W	1.000
12:117155934:C:T	C518Y	1.000
12:117155935:A:G	C518R	1.000
12:117157880:G:C	H511D	1.000
12:117157894:C:T	G506E	1.000
12:117146164:A:C	Y604D	0.999

dbSNP variants (sampled 300 via entrez): RS1000091136 (12:117190355 C>G,T), RS1000092165 (12:117149542 A>G), RS1000098367 (12:117183788 C>T), RS1000101860 (12:117144313 C>G,T), RS1000152550 (12:117144489 G>C), RS1000163463 (12:117191229 T>C,G), RS1000164652 (12:117150624 T>A,G), RS1000172052 (12:117173941 T>C,G), RS1000263553 (12:117191343 T>C), RS1000289169 (12:117154606 A>T), RS1000345332 (12:117156841 G>C), RS1000444624 (12:117190031 CG>C), RS1000452799 (12:117184909 C>G,T), RS1000510794 (12:117172781 T>C), RS1000521567 (12:117142893 A>G)

Disease associations

OMIM: gene MIM:609095 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006940_133	Neurociticism	3.000000e-09
GCST010083_254	Hemoglobin levels	1.000000e-11
GCST90002383_17	Hematocrit	2.000000e-12
GCST90002384_320	Hemoglobin	4.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0004509	hemoglobin measurement
EFO:0004348	hematocrit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs149212925	FBXO21	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects expression, decreases expression	3
Cyclosporine	decreases expression	2
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Diethylstilbestrol	increases expression	1
Ivermectin	decreases expression	1
Ketoconazole	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Vitamin K 3	affects expression	1

Clinical trials (associated diseases)

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