FBXO7

Summary

FBXO7 (F-box protein 7, HGNC:13586) is a protein-coding gene on chromosome 22q12.3, encoding F-box only protein 7 (Q9Y3I1). Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins and plays a role in several biological processes such as cell cycle, cell proliferat….

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 the 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 and it may play a role in regulation of hematopoiesis. Alternatively spliced transcript variants of this gene have been identified with the full-length natures of only some variants being determined.

Source: NCBI Gene 25793 — RefSeq curated summary.

At a glance

• Gene–disease (curated): parkinsonian-pyramidal syndrome (Strong, GenCC)
• GWAS associations: 16
• Clinical variants (ClinVar): 492 total — 31 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 37
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_012179

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13586
Approved symbol	FBXO7
Name	F-box protein 7
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	FBX7, Fbx, PARK15
Ensembl gene	ENSG00000100225
Ensembl biotype	protein_coding
OMIM	605648
Entrez	25793

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000266087, ENST00000397426, ENST00000420700, ENST00000425028, ENST00000444207, ENST00000452138, ENST00000465418, ENST00000484607, ENST00000492535, ENST00000886522, ENST00000886523, ENST00000886524, ENST00000920428

RefSeq mRNA: 3 — MANE Select: NM_012179 NM_001033024, NM_001257990, NM_012179

CCDS: CCDS13907, CCDS46695, CCDS58806

Canonical transcript exons

ENST00000266087 — 9 exons

Exon	Start	End
ENSE00003460199	32491086	32491181
ENSE00003492846	32493105	32493281
ENSE00003506260	32495493	32495530
ENSE00003509573	32498144	32498829
ENSE00003590976	32483897	32484124
ENSE00003618643	32485068	32485209
ENSE00003626183	32487745	32487828
ENSE00003635123	32478981	32479275
ENSE00003851044	32474811	32475124

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 89.2662 / max 6619.0998, expressed in 1825 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191874	31.4932	1782
191868	28.7621	1814
191869	16.9853	1796
191872	10.0556	1785
191870	0.6630	404
191876	0.4003	196
191871	0.2973	173
191877	0.2812	85
191873	0.1685	37
191878	0.1344	48

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	99.09	gold quality
blood	UBERON:0000178	98.80	gold quality
sperm	CL:0000019	98.44	gold quality
male germ cell	CL:0000015	98.36	gold quality
corpus callosum	UBERON:0002336	98.26	gold quality
bone marrow	UBERON:0002371	98.17	gold quality
left lobe of thyroid gland	UBERON:0001120	98.15	gold quality
thyroid gland	UBERON:0002046	98.11	gold quality
right testis	UBERON:0004534	98.11	gold quality
middle frontal gyrus	UBERON:0002702	98.06	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.06	gold quality
left testis	UBERON:0004533	98.02	gold quality
type B pancreatic cell	CL:0000169	98.01	gold quality
right lobe of thyroid gland	UBERON:0001119	98.00	gold quality
spinal cord	UBERON:0002240	97.88	gold quality
monocyte	CL:0000576	97.75	gold quality
mononuclear cell	CL:0000842	97.70	gold quality
bone element	UBERON:0001474	97.66	gold quality
leukocyte	CL:0000738	97.62	gold quality
inferior vagus X ganglion	UBERON:0005363	97.61	gold quality
testis	UBERON:0000473	97.54	gold quality
islet of Langerhans	UBERON:0000006	97.37	gold quality
adrenal tissue	UBERON:0018303	97.25	gold quality
adult organism	UBERON:0007023	97.19	gold quality
right lung	UBERON:0002167	97.05	gold quality
subthalamic nucleus	UBERON:0001906	96.88	gold quality
substantia nigra	UBERON:0002038	96.71	gold quality
adult mammalian kidney	UBERON:0000082	96.65	gold quality
midbrain	UBERON:0001891	96.62	gold quality
right adrenal gland cortex	UBERON:0035827	96.55	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	140.60
E-CURD-112	yes	57.67
E-HCAD-6	yes	57.40
E-MTAB-10042	yes	34.27
E-MTAB-9067	yes	20.52
E-MTAB-9221	yes	18.81
E-MTAB-5061	yes	14.18
E-HCAD-9	yes	10.41
E-HCAD-10	yes	5.15
E-MTAB-9467	yes	4.51
E-MTAB-6379	no	1225.43
E-GEOD-100618	no	500.33
E-MTAB-6142	no	339.55
E-MTAB-6524	no	103.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, PHB1

miRNA regulators (miRDB)

23 targeting FBXO7, 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-3646	100.00	73.56	5283
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-6874-5P	95.73	64.94	545
HSA-MIR-4633-3P	93.85	63.56	534
HSA-MIR-6500-5P	93.85	63.64	522

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-phosphorylated hepatoma up-regulated protein (HURP) proteolysis by a proline-rich region (PMID:15145941)
• a model for FP domain-mediated dimerization of SCF(Fbxo7) and PI31 (PMID:18495667)
• Recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. (PMID:19038853)
• FBXO7 mutations may be rare in Chinese early-onset Parkinsonism patients. (PMID:20603184)
• We identified genetic deficits in FBXO7 that were associated with Levodopa responsive parkinsonism with pyramidal signs. (PMID:20669327)
• activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15 (PMID:21347293)
• Skp1 binding prevented Fbxo7 from contacting CRM1. (PMID:21378169)
• Fbxo7 negatively regulates the proliferation and differentiation of haematopoietic progenitor cells in a p53-dependent manner (PMID:21695055)
• FBXO7 is a negative regulator of NF-KB signalling, modulating ubiquitination of several components of the TNF-R1 signalling complex and ultimately lowering NF-KB signalling activity. (PMID:22212761)
• The SNPs investigated in the BST1, PARK15 and PARK9 genes associated with PD susceptibility are not associated with PD in the northern Han Chinese population. (PMID:22490479)
• analysis of the zebrafish model of Fbxo7 mutations with a role in levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons (PMID:23133663)
• Mutations in FBX07 is often associated with rapidly progressive parkinsonism and with additional features including pyramidal signs, cognitive decline and loss of sustained Levodopa responsiveness. (PMID:23196729)
• [review] PARK15-associated parkinsonism, also referred to as parkinsonian-pyramidal disease (PPD), is caused by mutations in the F-box only protein 7 gene FBXO7. (PMID:23318512)
• A mutational analysis of the FBXO7 gene in Taiwanese patients with Parkinson’s disease (PD) does not show a potential pathophysiological role in PD. (PMID:23352116)
• An important role is suggested for FBXO7 in the pathogenesis of synucleinopathies, including Parkinson’s disease and multiple system atrophy. (PMID:23656991)
• This study showed that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy. (PMID:23933751)
• The involvement of the FBXO7 gene in PD is very rare, at least in this population from southern Spain. (PMID:24112787)
• The crystal structure of the Fbxo7 FP domain is reported at 2.0 A resolution. The Fbxo7 FP domain adopts an alpha/beta-fold similar to that of the PI31 FP domain. (PMID:24419388)
• Cys52 variant of FBXO7 may contribute to reduced Parkinson’s disease susceptibility in Chinese (PMID:25029497)
• genetic analysis of this Turkish family and the Italian PARK15 family reported previously revealed that the c.1492C > T mutation is present on two different haplotypes in the Italian family (PMID:25085748)
• in addition to the parkinsonian-pyramidal phenotype, in connection with FBXO7 mutations and points to an intrafamilial phenotypic variation (PMID:25169713)
• This is first time a FBXO7 mutation has been identified that causes phenotype compatible with typical idiopathic Parkinson’s disease and presents with some of its common nonmotor features (PMID:26010069)
• High expression of PARK15 might lead to the occurrence of non-small-cell lung cancer. (PMID:26245297)
• The mutations of F-box protein 7 (FBXO7) gene (T22M, R378G and R498X) are associated with autosomal recessive juvenile-onset Parkinson’s disease We demonstrated wild-type FBXO7 is a stress response protein with both cytoprotective and neurotoxic roles (PMID:26310625)
• Mutations in the F-box only protein 7 (FBXO7) gene, located on chromosome 22q12-q13, have been identified as having distinct clinical features in patients with hereditary Parkinson’s disease (PD). (PMID:26882974)
• Structure and function of Fbxo7 in Parkinson’s disease has been summarized. (Review) (PMID:26965690)
• Gsk3beta and Tomm20 are substrates of the SCFFbxo7/PARK15 ubiquitin ligase associated with Parkinson’s disease (PMID:27503909)
• Fbxo7 deficiency is associated with reduced cellular NAD(+) levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain. (PMID:27689878)
• we highlight the recent research on FBXO7, which advances our knowledge of the etiopathological pathways and fills unexpected gaps therein, justifying the dedicated study of rare variants of Parkinson disease–{REVIEW} (PMID:29134665)
• Results suggest that FBXO7 gene doesn’t seem to be a risk factor to develop sporadic Parkinson’s disease in Chinese population. (PMID:30232368)
• The pathological mechanisms concerning FBXO7-relevant protein aggregation, mitochondria impairment, reactive oxygen species (ROS) generation and mitophagy modulation in PARK15 pathogenesis are highlighted and discussed in the current review. (PMID:30454685)
• Compound heterozygous variants of the FBXO7 gene resulting in infantile-onset Parkinsonian-pyramidal syndrome in siblings of a Chinese family. (PMID:32274857)
• Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1. (PMID:32493843)
• The p105 NF-kB precursor is a pseudo substrate of the ubiquitin ligase FBXO7, and its binding to the ligase stabilizes it and results in stimulated cell proliferation. (PMID:32933748)
• Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson’s disease. (PMID:33002721)
• The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-kappaB signaling pathway. (PMID:33010352)
• Fbxo7 and Pink1 play a reciprocal role in regulating their protein levels. (PMID:33291077)
• Analysis of the FBXO7 promoter reveals overlapping Pax5 and c-Myb binding sites functioning in B cells. (PMID:33774278)
• The F-box protein, FBXO7, is required to maintain chromosome stability in humans. (PMID:34791250)
• FBXO7 triggers caspase 8-mediated proteolysis of the transcription factor FOXO4 and exacerbates neuronal cytotoxicity. (PMID:34800438)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo7	ENSDARG00000099833
mus_musculus	Fbxo7	ENSMUSG00000001786
rattus_norvegicus	Fbxo7	ENSRNOG00000004637

Protein

Protein identifiers

F-box only protein 7 — Q9Y3I1 (reviewed: Q9Y3I1)

All UniProt accessions (4): Q9Y3I1, A2A282, F8WBR0, F8WDR9

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins and plays a role in several biological processes such as cell cycle, cell proliferation, or maintenance of chromosome stability. Recognizes and ubiquitinates BIRC2 and the cell cycle regulator DLGAP5. Plays a role downstream of PINK1 in the clearance of damaged mitochondria via selective autophagy (mitophagy) by targeting PRKN to dysfunctional depolarized mitochondria. Promotes MFN1 ubiquitination. Mediates the ubiquitination and proteasomal degradation of UXT isoform 2, thereby impairing the NF-kappa-B signaling pathway. Inhibits NF-kappa-B pathway also by promoting the ubiquitination of TRAF2. Affects the assembly state and activity of the proteasome in the cells including neurons by ubiquitinating the proteasomal subunit PSMA2 via ‘Lys-63’-linked polyubiquitin chains. Promotes ‘Lys-48’-linked polyubiquitination SIRT7, leading to the hydrogen peroxide-induced cell death.

Subunit / interactions. Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7. Interacts via its C-terminal proline-rich region with DLGAP5. Interacts with BIRC2. Interacts with CDK6 and promotes its interaction with D-type cyclin. Interacts with PSMF1. Interacts (via the N-terminal Ubl domain) with PRKN. Interact (via N-terminal region) with PINK1. Interact (via N-terminal region) with PINK1.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion. Cytosol.

Disease relevance. Parkinson disease 15 (PARK15) [MIM:260300] A neurodegenerative disorder characterized by parkinsonian and pyramidal signs. Clinical manifestations include tremor, bradykinesia, rigidity, postural instability, spasticity, mainly in the lower limbs, and hyperreflexia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ubiquitin-like region mediates interaction with PRKN. The proline-rich region is important for protein-protein interactions.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y3I1-1	1	yes
Q9Y3I1-2	2
Q9Y3I1-3	3

RefSeq proteins (3): NP_001028196, NP_001244919, NP_036311* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR021625	PI31_Prot_N	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR047118	Fbxo7	Family

Pfam: PF11566, PF12937

UniProt features (47 total): sequence conflict 9, helix 8, region of interest 7, strand 6, sequence variant 4, modified residue 3, splice variant 3, mutagenesis site 2, chain 1, domain 1, compositionally biased region 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4L9H	X-RAY DIFFRACTION	2
4L9C	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3I1-F1	67.13	0.13

Functional residue map

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

Post-translational modifications (3): 432, 451, 518

Mutagenesis-validated functional residues (2):

Position	Phenotype
22	impairs interaction with prkn.
253	abolishes interaction with psmf1.

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: 310 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_MACROAUTOPHAGY, GNF2_ANK1

GO Biological Process (18): autophagy of mitochondrion (GO:0000422), ubiquitin-dependent protein catabolic process (GO:0006511), obsolete protein targeting to mitochondrion (GO:0006626), regulation of neuron projection development (GO:0010975), protein ubiquitination (GO:0016567), lymphocyte differentiation (GO:0030098), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), regulation of protein stability (GO:0031647), regulation of locomotion (GO:0040012), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of lymphocyte differentiation (GO:0045620), protein K48-linked ubiquitination (GO:0070936), positive regulation of mitophagy (GO:1901526), negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway (GO:1903377), positive regulation of autophagy of mitochondrion (GO:1903599), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134), negative regulation of neuron apoptotic process (GO:0043524)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), protein kinase binding (GO:0019901), ubiquitin protein ligase binding (GO:0031625), ubiquitin binding (GO:0043130), protein heterodimerization activity (GO:0046982), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (13): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), protein-containing complex (GO:0032991), glial cytoplasmic inclusion (GO:0097409), classical Lewy body (GO:0097414), Lewy neurite (GO:0097462), Lewy body core (GO:1990037), Lewy body corona (GO:1990038)

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
cellular anatomical structure	5
Lewy body	3
intracellular membrane-bounded organelle	2
cytoplasm	2
autophagy	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
protein modification by small protein conjugation	1
lymphocyte activation	1
mononuclear cell differentiation	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of biological quality	1
locomotion	1
regulation of biological process	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
lymphocyte differentiation	1
regulation of lymphocyte differentiation	1
negative regulation of lymphocyte activation	1
negative regulation of leukocyte differentiation	1
protein polyubiquitination	1
mitophagy	1
positive regulation of macroautophagy	1
regulation of mitophagy	1
positive regulation of autophagy of mitochondrion	1
neuron intrinsic apoptotic signaling pathway in response to oxidative stress	1
negative regulation of neuron apoptotic process	1
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1
regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1
autophagy of mitochondrion	1
positive regulation of autophagy	1
regulation of autophagy of mitochondrion	1
G1/S transition of mitotic cell cycle	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G1/S phase transition	1

Protein interactions and networks

STRING

2456 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO7	PINK1	Q9BXM7	990
FBXO7	SKP1	P34991	946
FBXO7	PLA2G6	O60733	898
FBXO7	ATP13A2	Q9NQ11	884
FBXO7	PRKN	O60260	882
FBXO7	PARK7	Q99497	864
FBXO7	GIGYF2	Q6Y7W6	857
FBXO7	VPS35	Q96QK1	844
FBXO7	CUL1	Q13616	843
FBXO7	LRRK2	Q5S007	808
FBXO7	GBA1	P04062	785
FBXO7	UCHL1	P09936	776
FBXO7	HTRA2	O43464	773
FBXO7	DNAJC6	O75061	761
FBXO7	PSMF1	Q92530	714

IntAct

167 interactions, top by confidence:

A	B	Type	Score
PSMF1	FBXO7	psi-mi:“MI:0915”(physical association)	0.930
FBXO7	PSMF1	psi-mi:“MI:0915”(physical association)	0.930
SKP1	FBXO7	psi-mi:“MI:0915”(physical association)	0.900
FBXO7	SKP1	psi-mi:“MI:0914”(association)	0.900
SKP1	TTC9C	psi-mi:“MI:0914”(association)	0.870
COPS2	GPS1	psi-mi:“MI:0914”(association)	0.860
PSMA2	PSMA7	psi-mi:“MI:0914”(association)	0.850
PSMA5	PSMA7	psi-mi:“MI:0914”(association)	0.800
PSMB7	PSMA7	psi-mi:“MI:0914”(association)	0.790
MED22	MED19	psi-mi:“MI:0914”(association)	0.790
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
PSMB3	PSMA7	psi-mi:“MI:0914”(association)	0.770
PINK1	PRKN	psi-mi:“MI:0914”(association)	0.750
PRKN	PINK1	psi-mi:“MI:0914”(association)	0.750
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
PSMB2	PSMD11	psi-mi:“MI:0914”(association)	0.730
PSMB4	PSMA7	psi-mi:“MI:0914”(association)	0.730

BioGRID (784): FBXO7 (Reconstituted Complex), FBXO7 (Two-hybrid), FBXO7 (Two-hybrid), FBXO7 (Two-hybrid), FBXO7 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), ZBTB48 (Affinity Capture-MS), PRMT1 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS)

ESM2 similar proteins: A1L1P7, A4QP73, A8IYS6, B0BN56, C5DQ08, D3ZYW7, H2KZB2, O22288, O35658, O35796, O35943, O94675, P12617, P82925, P83093, P87127, Q05B87, Q07021, Q16595, Q1PF33, Q21018, Q2KI49, Q2T9S7, Q32PH2, Q3T0B6, Q3U7U3, Q54JD2, Q5REH5, Q5RJK8, Q5XF06, Q5ZLC1, Q61733, Q63798, Q66JD1, Q68FS3, Q6DKK2, Q756Q4, Q759J5, Q8JZS9, Q8N5N7

Diamond homologs: Q2T9S7, Q3U7U3, Q68FS3, Q9Y3I1

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
FBXO7	“down-regulates quantity by destabilization”	DLGAP5	binding
FBXO7	“up-regulates activity”	SCF-FBW7	binding
FBXO7	“down-regulates quantity by destabilization”	WDR62	ubiquitination
FBXO7	“down-regulates quantity by destabilization”	CRBN	binding
FBXO7	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 142 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
Antigen processing: Ub, ATP-independent proteasomal degradation	10	61.4×	2e-15
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	18	46.0×	7e-24
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	17	45.4×	2e-22
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	16	42.7×	6e-21
Proteasome assembly	19	41.7×	5e-24
Degradation of GLI2 by the proteasome	17	40.9×	9e-22
GLI3 is processed to GLI3R by the proteasome	17	40.9×	9e-22
Negative regulation of NOTCH4 signaling	16	40.9×	1e-20

GO biological processes:

GO term	Partners	Fold	FDR
protein neddylation	5	28.1×	2e-04
proteasome-mediated ubiquitin-dependent protein catabolic process	21	8.8×	2e-11
ubiquitin-dependent protein catabolic process	12	7.1×	6e-05
protein ubiquitination	12	4.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	7
Uncertain significance	149
Likely benign	219
Benign	35

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1455741	NM_012179.4(FBXO7):c.1213G>T (p.Glu405Ter)	Pathogenic
2032126	NM_012179.4(FBXO7):c.521C>A (p.Ser174Ter)	Pathogenic
2150213	NM_012179.4(FBXO7):c.269_270del (p.Ser90fs)	Pathogenic
2699868	NM_012179.4(FBXO7):c.575_576del (p.Cys192fs)	Pathogenic
2715290	NM_012179.4(FBXO7):c.1220del (p.Pro407fs)	Pathogenic
2725775	NM_012179.4(FBXO7):c.156C>G (p.Tyr52Ter)	Pathogenic
2732774	NM_012179.4(FBXO7):c.915_916del (p.Arg306fs)	Pathogenic
2751170	NM_012179.4(FBXO7):c.1A>G (p.Met1Val)	Pathogenic
2751184	NM_012179.4(FBXO7):c.497C>G (p.Ser166Ter)	Pathogenic
2752709	NM_012179.4(FBXO7):c.1188C>A (p.Tyr396Ter)	Pathogenic
2757154	NM_012179.4(FBXO7):c.544dup (p.Ser182fs)	Pathogenic
2765341	NM_012179.4(FBXO7):c.564_567del (p.Ser189fs)	Pathogenic
2796908	NM_012179.4(FBXO7):c.1344T>A (p.Tyr448Ter)	Pathogenic
2830552	NM_012179.4(FBXO7):c.316_317del (p.Leu106fs)	Pathogenic
2842805	NM_012179.4(FBXO7):c.925A>T (p.Lys309Ter)	Pathogenic
2884317	NM_012179.4(FBXO7):c.377del (p.Gly126fs)	Pathogenic
2887235	NM_012179.4(FBXO7):c.1A>C (p.Met1Leu)	Pathogenic
2900056	NM_012179.4(FBXO7):c.821_822del (p.Val274fs)	Pathogenic
2915527	NM_012179.4(FBXO7):c.1408G>T (p.Glu470Ter)	Pathogenic
2916108	NM_012179.4(FBXO7):c.2T>G (p.Met1Arg)	Pathogenic
2960440	NM_012179.4(FBXO7):c.893_894insT (p.Lys299fs)	Pathogenic
2960687	NM_012179.4(FBXO7):c.2T>A (p.Met1Lys)	Pathogenic
3247732	NC_000022.10:g.(?32894111)(32894517_?)del	Pathogenic
3247743	NC_000022.10:g.(?32891460)(32894517_?)del	Pathogenic
3627116	NM_012179.4(FBXO7):c.1044del (p.Asp348fs)	Pathogenic
3637878	NM_012179.4(FBXO7):c.749_750del (p.Leu250fs)	Pathogenic
3673551	NM_012179.4(FBXO7):c.366_367insC (p.Ser123fs)	Pathogenic
4808	NM_012179.4(FBXO7):c.1132C>G (p.Arg378Gly)	Pathogenic
4809	NM_012179.4(FBXO7):c.1492C>T (p.Arg498Ter)	Pathogenic
4810	NM_012179.4(FBXO7):c.1144+1G>T	Pathogenic

SpliceAI

1661 predictions. Top by Δscore:

Variant	Effect	Δscore
22:32475121:ACAG:A	donor_loss	1.0000
22:32475123:AGG:A	donor_loss	1.0000
22:32475125:GTACG:G	donor_loss	1.0000
22:32475126:T:A	donor_loss	1.0000
22:32479271:GTATG:G	donor_gain	1.0000
22:32483896:GTT:G	acceptor_gain	1.0000
22:32483896:GTTA:G	acceptor_gain	1.0000
22:32485054:A:AG	acceptor_gain	1.0000
22:32485054:ATTTC:A	acceptor_gain	1.0000
22:32485055:T:G	acceptor_gain	1.0000
22:32485058:C:A	acceptor_gain	1.0000
22:32485063:CCCA:C	acceptor_loss	1.0000
22:32485064:CCAG:C	acceptor_loss	1.0000
22:32485066:A:AG	acceptor_gain	1.0000
22:32485066:AG:A	acceptor_gain	1.0000
22:32485066:AGG:A	acceptor_gain	1.0000
22:32485066:AGGG:A	acceptor_loss	1.0000
22:32485067:G:GC	acceptor_loss	1.0000
22:32485067:G:GG	acceptor_gain	1.0000
22:32485067:GG:G	acceptor_gain	1.0000
22:32485067:GGG:G	acceptor_gain	1.0000
22:32485067:GGGC:G	acceptor_gain	1.0000
22:32487737:A:AG	acceptor_gain	1.0000
22:32487739:TTACA:T	acceptor_loss	1.0000
22:32487740:TACA:T	acceptor_loss	1.0000
22:32487741:ACAGC:A	acceptor_loss	1.0000
22:32487742:CA:C	acceptor_loss	1.0000
22:32487743:A:AG	acceptor_gain	1.0000
22:32487744:G:A	acceptor_loss	1.0000
22:32487744:G:GG	acceptor_gain	1.0000

AlphaMissense

3373 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:32493251:T:A	W372R	0.998
22:32493251:T:C	W372R	0.998
22:32495522:T:A	W392R	0.997
22:32495522:T:C	W392R	0.997
22:32493253:G:C	W372C	0.995
22:32493253:G:T	W372C	0.995
22:32491141:A:C	K309N	0.994
22:32491141:A:T	K309N	0.994
22:32493270:G:C	R378P	0.994
22:32495524:G:C	W392C	0.994
22:32495524:G:T	W392C	0.994
22:32498147:T:G	Y396D	0.994
22:32491140:A:T	K309I	0.992
22:32493141:T:A	L335H	0.992
22:32493153:T:C	L339P	0.992
22:32493192:T:A	V352D	0.992
22:32491176:G:C	R321P	0.991
22:32493159:T:C	L341P	0.991
22:32493252:G:C	W372S	0.991
22:32484093:T:C	L205P	0.990
22:32493263:T:G	Y376D	0.990
22:32493275:T:C	F380L	0.990
22:32493277:T:A	F380L	0.990
22:32493277:T:G	F380L	0.990
22:32479079:T:A	I74K	0.989
22:32485134:T:G	Y238D	0.989
22:32493141:T:C	L335P	0.989
22:32493141:T:G	L335R	0.988
22:32493144:C:G	P336R	0.988
22:32485104:T:A	W228R	0.987

dbSNP variants (sampled 300 via entrez): RS1000079620 (22:32474842 C>G,T), RS1000256093 (22:32475196 C>A,T), RS1000321900 (22:32486512 T>G), RS1000429860 (22:32475114 T>A,G), RS1000507851 (22:32493452 C>G), RS1000685195 (22:32498636 T>G), RS1000712471 (22:32474948 C>A,G,T), RS1000744428 (22:32481904 A>G), RS1000805934 (22:32481104 T>A), RS1000997220 (22:32476195 C>G,T), RS1001006051 (22:32487672 G>A), RS1001102219 (22:32493698 C>A), RS1001244540 (22:32474622 G>A), RS1001297034 (22:32474436 C>G), RS1001373491 (22:32487289 A>C,G,T)

Disease associations

OMIM: gene MIM:605648 | disease phenotypes: MIM:260300

GenCC curated gene-disease

Disease	Classification	Inheritance
parkinsonian-pyramidal syndrome	Strong	Autosomal recessive

Mondo (1): parkinsonian-pyramidal syndrome (MONDO:0009830)

Orphanet (1): Parkinsonian-pyramidal syndrome (Orphanet:171695)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000338	Hypomimic face
HP:0000514	Slow saccadic eye movements
HP:0000726	Dementia
HP:0001249	Intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001762	Talipes equinovarus
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002080	Intention tremor
HP:0002141	Gait imbalance
HP:0002172	Postural instability
HP:0002322	Resting tremor
HP:0002360	Sleep disturbance
HP:0002362	Shuffling gait
HP:0002367	Visual hallucination
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003487	Babinski sign
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0007256	Abnormal pyramidal sign

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001765_29	Red blood cell traits	3.000000e-13
GCST004601_206	Red blood cell count	1.000000e-13
GCST004602_246	Mean corpuscular volume	1.000000e-47
GCST004621_180	Red cell distribution width	7.000000e-21
GCST004630_38	Mean corpuscular hemoglobin	1.000000e-43
GCST005993_24	Mean corpuscular hemoglobin	5.000000e-15
GCST006011_1	Mean corpuscular volume	2.000000e-14
GCST010002_81	Refractive error	6.000000e-13
GCST90002390_317	Mean corpuscular hemoglobin	3.000000e-41
GCST90002390_318	Mean corpuscular hemoglobin	1.000000e-64
GCST90002392_134	Mean corpuscular volume	1.000000e-57
GCST90002396_88	Mean reticulocyte volume	3.000000e-46
GCST90002396_89	Mean reticulocyte volume	2.000000e-51
GCST90002397_600	Mean spheric corpuscular volume	7.000000e-47
GCST90002403_700	Red blood cell count	1.000000e-38
GCST90002404_401	Red cell distribution width	2.000000e-49

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538104	Pallidopyramidal syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
GSK-J4	increases expression	1
bisphenol F	affects cotreatment, increases methylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
methylparaben	increases expression	1
tetrabromobisphenol A	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
fenpyroximate	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
picoxystrobin	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Ivermectin	decreases expression	1
Rotenone	decreases expression	1
Thimerosal	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

11 cell lines: 5 embryonic stem cell, 3 cancer cell line, 2 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C4EN	H9 AAVS1-TRE3G-NGN2 FBXO7-/-	Embryonic stem cell	Female
CVCL_C4ER	HeLa HFT/TO-PRKN FBXO7-/-	Cancer cell line	Female
CVCL_C7U0	HEK293T FBXO7-/-	Transformed cell line	Female
CVCL_C7V9	WIBRe001-A-10	Embryonic stem cell	Female
CVCL_C7VA	WIBR3_FBXO7_FS_B6-1	Embryonic stem cell	Female
CVCL_C7VB	WIBRe001-A-9	Embryonic stem cell	Female
CVCL_C7VC	WIBR3_FBXO7_R498X_G7-1	Embryonic stem cell	Female
CVCL_E4T3	KOLF2.1J FBXO7 I87T SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E4T4	KOLF2.1J FBXO7 I87T SNV/WT	Induced pluripotent stem cell	Male
CVCL_SN27	HAP1 FBXO7 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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