XPO5

Summary

XPO5 (exportin 5, HGNC:17675) is a protein-coding gene on chromosome 6p21.1, encoding Exportin-5 (Q9HAV4). Mediates the nuclear export of proteins bearing a double-stranded RNA binding domain (dsRBD) and double-stranded RNAs (cargos). It is a selective cancer dependency (DepMap: 80.5% of cell lines).

This gene encodes a member of the karyopherin family that is required for the transport of small RNAs and double-stranded RNA-binding proteins from the nucleus to the cytoplasm. The encoded protein translocates cargo through the nuclear pore complex in a RanGTP-dependent process.

Source: NCBI Gene 57510 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome (Limited, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 144 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 80.5% of screened cell lines
• MANE Select transcript: NM_020750

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17675
Approved symbol	XPO5
Name	exportin 5
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1291
Ensembl gene	ENSG00000124571
Ensembl biotype	protein_coding
OMIM	607845
Entrez	57510

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 10 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000265351, ENST00000398799, ENST00000398835, ENST00000424378, ENST00000450462, ENST00000455285, ENST00000455854, ENST00000486936, ENST00000488195, ENST00000496341, ENST00000513451, ENST00000612911, ENST00000943408, ENST00000943409, ENST00000943410, ENST00000943411, ENST00000943412, ENST00000943413, ENST00000943414, ENST00000943415

RefSeq mRNA: 1 — MANE Select: NM_020750 NM_020750

CCDS: CCDS47430

Canonical transcript exons

ENST00000265351 — 32 exons

Exon	Start	End
ENSE00002034469	43527634	43527731
ENSE00002071459	43522334	43524005
ENSE00002324545	43547608	43547707
ENSE00002391501	43549489	43549578
ENSE00002423051	43548261	43548460
ENSE00002449061	43560924	43561007
ENSE00002461197	43568711	43568737
ENSE00002466432	43562247	43562346
ENSE00002485620	43570857	43570994
ENSE00002495098	43573480	43573601
ENSE00002498447	43570502	43570684
ENSE00002513572	43565660	43565736
ENSE00002513716	43560178	43560303
ENSE00002532204	43567169	43567354
ENSE00002717198	43575760	43576038
ENSE00003478876	43558501	43558591
ENSE00003490117	43528159	43528205
ENSE00003490579	43530688	43530824
ENSE00003495775	43546571	43546752
ENSE00003514702	43528828	43528925
ENSE00003583426	43525107	43525214
ENSE00003590705	43572506	43572578
ENSE00003598680	43525839	43525921
ENSE00003601003	43549893	43549934
ENSE00003621574	43553373	43553503
ENSE00003625634	43531479	43531575
ENSE00003628244	43551298	43551453
ENSE00003649777	43524471	43524635
ENSE00003667367	43524831	43524968
ENSE00003669826	43555836	43555964
ENSE00003671979	43533907	43534007
ENSE00003681277	43526685	43526747

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 94.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.7735 / max 187.9243, expressed in 1817 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73704	25.1600	1817
73703	1.0370	545
73702	0.4739	219
73700	0.1026	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	94.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.30	gold quality
upper arm skin	UBERON:0004263	93.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.48	gold quality
pancreatic ductal cell	CL:0002079	91.97	silver quality
left testis	UBERON:0004533	91.73	gold quality
right testis	UBERON:0004534	91.54	gold quality
cortical plate	UBERON:0005343	91.27	gold quality
body of pancreas	UBERON:0001150	91.25	gold quality
testis	UBERON:0000473	91.09	gold quality
embryo	UBERON:0000922	90.97	gold quality
ganglionic eminence	UBERON:0004023	90.97	gold quality
ventricular zone	UBERON:0003053	90.46	gold quality
bone marrow cell	CL:0002092	90.26	gold quality
kidney epithelium	UBERON:0004819	90.01	gold quality
pancreas	UBERON:0001264	89.84	gold quality
skin of leg	UBERON:0001511	89.33	gold quality
lower esophagus mucosa	UBERON:0035834	89.09	gold quality
colonic epithelium	UBERON:0000397	88.64	gold quality
right lobe of thyroid gland	UBERON:0001119	88.55	gold quality
islet of Langerhans	UBERON:0000006	88.54	gold quality
skin of abdomen	UBERON:0001416	88.54	gold quality
left lobe of thyroid gland	UBERON:0001120	88.37	gold quality
zone of skin	UBERON:0000014	88.05	gold quality
metanephros	UBERON:0000081	88.05	gold quality
thyroid gland	UBERON:0002046	87.71	gold quality
esophagus mucosa	UBERON:0002469	87.58	gold quality
stromal cell of endometrium	CL:0002255	87.46	gold quality
cartilage tissue	UBERON:0002418	87.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting XPO5, 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-4533	100.00	69.48	2758
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-6733-5P	99.74	67.94	2759

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 80.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport pathways to confine translation to the cytoplasm. (PMID:12426392)
• Eukaryotic elongation factor 1A (eEF1A) and tRNA are RanGTP-dependent binding partners of exportin-5 (Exp5). Exp5 stimulates nuclear export of eEF1A and tRNA. (PMID:12426393)
• exportin-5 has a role in nuclear export of ILF3 (interleukin enhancer binding factor 3) (PMID:14570900)
• exportin-5 is key to microRNA biogenesis and may help coordinate nuclear and cytoplasmic processing steps (PMID:14631048)
• exportin-5 has a role in exporting JAZ from the cell nucleus (PMID:15254228)
• Each of the dsRBDs in ADAR1 interacts with the export factor exportin-5. (PMID:19124606)
• 2.9 angstrom structure of the pre-miRNA nuclear export machinery formed by pre-miRNA complexed with Exp-5 and RanGTP; RNA recognition by Exp-5:RanGTP does not depend on RNA sequence, implying that Exp-5:RanGTP can recognize a variety of pre-miRNAs (PMID:19965479)
• The restoration of XPO5 functions reverses the impaired export of pre-miRNAs and has tumor-suppressor features. (PMID:20951941)
• Data show a requirement for the export receptor Exportin 5 in nuclear export of 60S subunits in human cells, and that Exp5 binds to pre-60S particles in a RanGTP-dependent manner. (PMID:21048991)
• Exportin-5 controls Dicer1 expression post-transcriptionally. (PMID:21297638)
• overall survival was significantly longer in multiple myeloma patients with C/C or A/C variant in the XPO5 gene single nucleotide polymorphism site rs11077 (PMID:22539802)
• Dicer, Drosha, and Exportin 5 genes were up-regulated in bladder urothelial carcinoma compared to normal urothelium. Silencing these genes induced cell proliferation inhibition and apoptosis in bladder urothelial carcinoma cells. (PMID:22766726)
• data demonstrate that the exportin 5 (XPO5) rs2257082 T variant allele occurs more frequently in primary ovarian insufficiency (POI)patients than in controls, suggesting that this allele may be associated with increased POI risk (PMID:23549446)
• The study identifies a miR-138-RMND5A-Exportin-5 as a previously unknown miRNA processing regulatory pathway in HeLa cells. (PMID:24057215)
• eEF1A binds to Snail transcription factors when bound to their main target, the E-cadherin promoter, facilitating their export to the cytoplasm in association with the aa-tRNA-Exportin5 complex. (PMID:24209753)
• Knockdown of exportins 4, 5, and 7 altered thyroid hormone receptor shuttling dynamics, and when exportins 5 and 7 were overexpressed, TR distribution shifted toward the cytosol. (PMID:25911113)
• Variations in XPO5 rs11077 of Korean patients are significantly associated with their risk of colorectal cancer. (PMID:26147304)
• The microRNA-related single-nucleotide polymorphisms rs11077 of XPO5 may be independently connected with the prognosis and chemotherapy response of advanced non-small-cell lung cancer patients (PMID:26358254)
• NUP93 and exportin 5 interact with the signaling protein SMAD4 and that NUP93 mutations abrogated interaction with SMAD4 (PMID:26878725)
• XPO5 role in microRNA biogenesis (PMID:26976605)
• findings suggest that XPO5 functions as a potential tumor suppressor in the development and progression of HCC as well as a promising molecular target for HCC therapy (PMID:27000860)
• XPO5 acts like an oncogene in colorectal cancer by regulating the expression of miRNAs and may be a potential therapeutic target in colorectal cancer (PMID:27553833)
• Aberrant XPO5 expression is important for the maturation of miRNAs and the malignant behavior of melanoma cells. High abundance of XPO5 in melanoma leads to enhanced survival, proliferation and metastasis. (PMID:27556702)
• one SNP in XPO5 extron (rs2257082) was significantly associated with lead-poisoning; there were no significant association between the other six SNPs and the blood lead levels; polymorphism rs2257082 could be used to distinguish lead-resistant and lead-susceptible populations (PMID:28042866)
• SNP rs11077 influences the expression of XPO5, and this SNP could also be a potential biomarker for the diagnosis of thyroid cancer, especially in Chinese population (PMID:28383405)
• data strongly strengthened the notion that phosphorylation of XPO5 by ERK downregulates miRNA expression in clinical samples and is correlated with poor clinical outcomes of HCC patients (PMID:28500493)
• overexpression of XPO5 causes dysregulation in the miRNA processing mechanism, resulting in a shift in protein stability via lower ubiquitination and hyper N-linked glycosylation, as well as conferring a growth advantage by suppressing the DNA damage response. (PMID:28881308)
• DICER rs3742330 AG+GG genotype was associated with more advanced T stage compared to AA genotype ( P=0.009). More patients with XPO5 rs2257082 CC genotype had poorly differentiated tumors compared with CT+TT genotype carriers..), carriers of RAN rs14035 CC genotype had higher three-year OS rate than carriers of CT+TT genotype (adjusted HR 3.174; 95% CI 1.010, 9.973; P=0.048). (PMID:29683064)
• XPO5 might have a dual role in promoting or inhibiting tumor growth in different cancer tissue types. (PMID:29699373)
• XPO5 is a key factor in this process. (PMID:29790454)
• Two X-ray structures for Exp-5 alone and Exp-5:RanGTP intermediate complex were analyzed. Exp-5 adopts a ring-shaped closed conformation by C-terminal anchor residues 1,167-1,179, interacting with N-terminal heat repeats 4-9. This form is important for the stability of the cargo-free state. Interaction between Exp-5 and RanGTP induces elimination of intramolecular contacts of the C-terminal anchor. (PMID:30100359)
• Genetic polymorphisms in DICER and XPO5 genes are associated with a decreased risk of coronary artery disease, probably by impacting expression levels of vascular and cardiac-specific miRNAs. (PMID:31185329)
• describe a molecular pathway for the delivery of microRNA (miRNA) cargo to nascent tumour-derived microvesicles involving the dissociation of a pre-miRNA/Exportin-5 complex from Ran-GTP following nuclear export and its subsequent transfer to a cytoplasmic shuttle comprised of ARF6-GTP and GRP1 (PMID:31235936)
• Association between Genetic Polymorphisms in microRNA Machinery Genes and Risk of Papillary Thyroid Carcinoma. (PMID:31250375)
• These finding showed no significant association between XPO5 rs11077 variant and overall cancer risk, either performed subgroup analysis by cancer types and ethnic groups in all genetic model. (PMID:31868332)
• Exportin-5 SUMOylation promotes hepatocellular carcinoma progression. (PMID:32763246)
• Analysis of microRNA processing machinery gene (DROSHA, DICER1, RAN, and XPO5) variants association with end-stage renal disease. (PMID:32770606)
• Effects of Knockdown of XPO5 by siRNA on the Biological Behavior of Head and Neck Cancer Cells. (PMID:34328643)
• Selectivity of Exportin 5 binding to human precursor microRNAs. (PMID:34592896)
• The impact of Dicer, Drosha, and Exportin-5 levels in polycystic ovary syndrome (PCOS) diagnosis and phenotyping. (PMID:34855193)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	xpo5	ENSDARG00000098868
danio_rerio		ENSDARG00000112522
mus_musculus	Xpo5	ENSMUSG00000067150
rattus_norvegicus	Xpo5	ENSRNOG00000019085
drosophila_melanogaster	Ranbp21	FBGN0031051

Paralogs (1): XPO1 (ENSG00000082898)

Protein

Protein identifiers

Exportin-5 — Q9HAV4 (reviewed: Q9HAV4)

Alternative names: Ran-binding protein 21

All UniProt accessions (6): E2QRM3, Q9HAV4, H0Y3Q8, H0Y3W3, H0Y9I3, H0YA57

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the nuclear export of proteins bearing a double-stranded RNA binding domain (dsRBD) and double-stranded RNAs (cargos). XPO5 in the nucleus binds cooperatively to the RNA and to the GTPase Ran in its active GTP-bound form. Proteins containing dsRBDs can associate with this trimeric complex through the RNA. Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause disassembly of the complex and release of the cargo from the export receptor. XPO5 then returns to the nuclear compartment by diffusion through the nuclear pore complex, to mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Overexpression may in some circumstances enhance RNA-mediated gene silencing (RNAi). Mediates nuclear export of isoform 5 of ADAR/ADAR1 in a RanGTP-dependent manner. Mediates the nuclear export of micro-RNA precursors, which form short hairpins. Also mediates the nuclear export of synthetic short hairpin RNAs used for RNA interference. In some circumstances can also mediate the nuclear export of deacylated and aminoacylated tRNAs. Specifically recognizes dsRNAs that lack a 5’-overhang in a sequence-independent manner, have only a short 3’-overhang, and that have a double-stranded length of at least 15 base-pairs. Binding is dependent on Ran-GTP. (Microbial infection) Mediates the nuclear export of adenovirus VA1 dsRNA.

Subunit / interactions. Component of a nuclear export receptor complex composed of XPO5, RAN, dsRNA-binding proteins and dsRNA. Found in a nuclear export complex with XPO5, RAN, EEF1A1, and aminoacylated tRNA. Found in a nuclear export complex with XPO5, RAN, ILF3 and dsRNA. Found in a nuclear export complex with XPO5, RAN and pre-miRNA. Found in a nuclear export complex with XPO5, RAN, ILF3 and minihelix VA1 dsRNA. Found in a nuclear export complex with XPO5, RAN, ILF3, ZNF346 and dsRNA. Interacts with EEF1A1, ILF3, NUP153, NUP214 and ZNF346. Interacts with RAN and cargo proteins in a GTP-dependent manner. Interacts with isoform 5 of ADAR/ADAR1 (via DRBM domains). Interacts with SMAD4; mediates nuclear export of SMAD4. Interacts with RAN (GTP-bound form).

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in heart, brain, placenta, lung, skeletal muscle, kidney and pancreas.

Similarity. Belongs to the exportin family.

RefSeq proteins (1): NP_065801* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001494	Importin-beta_N	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR013598	Exportin-1/Importin-b-like	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR045065	XPO1/5	Family
IPR045478	Exportin-5_C	Domain

Pfam: PF03810, PF08389, PF19273

UniProt features (109 total): helix 65, turn 15, strand 10, sequence conflict 4, site 4, modified residue 3, sequence variant 3, region of interest 3, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3A6P	X-RAY DIFFRACTION	2.92
5YU6	X-RAY DIFFRACTION	3
5YU7	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAV4-F1	88.01	0.70

Functional residue map

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

Catalytic / active sites (4): 441 (pre-mirna binding); 448 (pre-mirna binding); 718 (pre-mirna binding); 1045 (pre-mirna binding)

Post-translational modifications (3): 396, 826, 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-203927	MicroRNA (miRNA) biogenesis

MSigDB gene sets: 140 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, CMYB_01, TTTGTAG_MIR520D, CGGAARNGGCNG_UNKNOWN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, AP2_Q3, GOMF_GTPASE_BINDING, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, PATIL_LIVER_CANCER, GOBP_NUCLEAR_TRANSPORT, GTGCCTT_MIR506, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, MARTINEZ_RB1_TARGETS_DN, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT

GO Biological Process (7): RNA export from nucleus (GO:0006405), protein export from nucleus (GO:0006611), miRNA metabolic process (GO:0010586), pre-miRNA export from nucleus (GO:0035281), intracellular protein transport (GO:0006886), protein transport (GO:0015031), regulatory ncRNA-mediated gene silencing (GO:0031047)

GO Molecular Function (8): tRNA binding (GO:0000049), RNA binding (GO:0003723), mRNA binding (GO:0003729), nuclear export signal receptor activity (GO:0005049), small GTPase binding (GO:0031267), pre-miRNA binding (GO:0070883), RISC complex binding (GO:1905172), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), RISC complex (GO:0016442), RNA nuclear export complex (GO:0042565)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gene Silencing by RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear export	3
RNA binding	3
cellular anatomical structure	3
intracellular protein localization	2
RNA transport	1
intracellular protein transport	1
RNA metabolic process	1
RNA export from nucleus	1
miRNA-mediated post-transcriptional gene silencing	1
protein transport	1
intracellular transport	1
transport	1
establishment of protein localization	1
negative regulation of gene expression	1
nucleic acid binding	1
nucleocytoplasmic carrier activity	1
GTPase binding	1
ribonucleoprotein complex binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
RNAi effector complex	1
nucleocytoplasmic transport complex	1

Protein interactions and networks

STRING

3122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XPO5	RAN	P17080	999
XPO5	DICER1	Q9UPY3	955
XPO5	DROSHA	Q9NRR4	939
XPO5	DGCR8	Q8WYQ5	924
XPO5	AGO2	Q9UKV8	899
XPO5	TARBP2	Q15633	886
XPO5	ILF3	Q12906	869
XPO5	NUP153	P49790	837
XPO5	RANGAP1	P46060	811
XPO5	AGO1	Q9UL18	786
XPO5	RNH1	P13489	776
XPO5	XPO1	O14980	724
XPO5	XPOT	O43592	704
XPO5	IPO8	O15397	691
XPO5	CSE1L	P55060	689

IntAct

202 interactions, top by confidence:

A	B	Type	Score
HRAS	RAF1	psi-mi:“MI:0914”(association)	0.980
SMARCB1	ARID1A	psi-mi:“MI:0914”(association)	0.860
RAB11A	EVI5	psi-mi:“MI:0914”(association)	0.800
STBD1	GABARAP	psi-mi:“MI:0914”(association)	0.760
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NME3	NME4	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
	XPO5	psi-mi:“MI:0403”(colocalization)	0.610
	RAN	psi-mi:“MI:0915”(physical association)	0.590
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
KLK6	XPO5	psi-mi:“MI:0915”(physical association)	0.560
XPO5		psi-mi:“MI:0915”(physical association)	0.550
NCR3LG1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
VSIG2	TTI1	psi-mi:“MI:0914”(association)	0.530
RALB	DBT	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530

BioGRID (296): XPO5 (Affinity Capture-RNA), XPO5 (Affinity Capture-RNA), XPO5 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), NUP98 (Co-fractionation), PPME1 (Co-fractionation), XPO5 (Co-fractionation), XPO5 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), XPO5 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4ITC5, A1L1F4, A4L9P7, E9Q8I9, F1MKX4, F1QFR9, F1R2X6, F8VPU6, O94915, P21359, P42345, P42346, P51593, P97526, Q04690, Q14997, Q29RF7, Q2HJG5, Q498H0, Q4KLU7, Q4QXM3, Q4VA53, Q5F3U9, Q5F3V3, Q5R6J0, Q5SSW2, Q5TBA9, Q5U241, Q5VYK3, Q6A026, Q6DDM4, Q6GP04, Q6NRP2, Q6P4S8, Q6PDI5, Q6TRW4, Q7PX35, Q7TMY8, Q7Z3U7, Q7Z6Z7

Diamond homologs: Q924C1, Q9HAV4

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
MAPK1	“down-regulates activity”	XPO5	phosphorylation
MAPK3	“down-regulates activity”	XPO5	phosphorylation
ERK1/2	“down-regulates activity”	XPO5	phosphorylation
PIN1	“down-regulates activity”	XPO5	isomerization
Gbeta	“down-regulates activity”	XPO5	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	54
Benign	34

Top pathogenic / likely-pathogenic (0)

SpliceAI

5077 predictions. Top by Δscore:

Variant	Effect	Δscore
6:43524004:TT:T	acceptor_gain	1.0000
6:43524006:C:CC	acceptor_gain	1.0000
6:43524466:CCTA:C	donor_loss	1.0000
6:43524467:CTA:C	donor_loss	1.0000
6:43524468:TA:T	donor_loss	1.0000
6:43524469:A:AC	donor_gain	1.0000
6:43524469:A:C	donor_loss	1.0000
6:43524469:AC:A	donor_gain	1.0000
6:43524469:ACC:A	donor_gain	1.0000
6:43524470:C:CC	donor_gain	1.0000
6:43524470:CC:C	donor_gain	1.0000
6:43524470:CCC:C	donor_gain	1.0000
6:43524633:GCG:G	acceptor_gain	1.0000
6:43524634:CG:C	acceptor_gain	1.0000
6:43524634:CGC:C	acceptor_gain	1.0000
6:43524829:A:AC	donor_gain	1.0000
6:43524830:C:CC	donor_gain	1.0000
6:43524965:GCAC:G	acceptor_gain	1.0000
6:43524966:CAC:C	acceptor_gain	1.0000
6:43524966:CACC:C	acceptor_gain	1.0000
6:43524967:AC:A	acceptor_gain	1.0000
6:43524968:CC:C	acceptor_gain	1.0000
6:43524969:C:CC	acceptor_gain	1.0000
6:43524970:T:A	acceptor_loss	1.0000
6:43525104:TACTT:T	donor_loss	1.0000
6:43525105:A:AC	donor_gain	1.0000
6:43525106:C:CA	donor_loss	1.0000
6:43525106:C:CC	donor_gain	1.0000
6:43525210:ACATC:A	acceptor_gain	1.0000
6:43525211:CATC:C	acceptor_gain	1.0000

AlphaMissense

7939 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:43570913:A:G	W128R	1.000
6:43570913:A:T	W128R	1.000
6:43570918:C:G	R126P	1.000
6:43572571:A:G	W79R	1.000
6:43572571:A:T	W79R	1.000
6:43525163:C:G	D1040H	0.999
6:43528190:A:G	W931R	0.999
6:43528190:A:T	W931R	0.999
6:43549538:G:T	A604D	0.999
6:43549547:C:A	R601M	0.999
6:43549547:C:G	R601T	0.999
6:43560276:A:G	W375R	0.999
6:43560276:A:T	W375R	0.999
6:43567191:A:G	L271P	0.999
6:43567294:A:G	W237R	0.999
6:43567294:A:T	W237R	0.999
6:43570601:T:A	R174S	0.999
6:43570601:T:G	R174S	0.999
6:43570644:A:G	L160P	0.999
6:43570901:A:G	W132R	0.999
6:43570901:A:T	W132R	0.999
6:43570911:C:A	W128C	0.999
6:43570911:C:G	W128C	0.999
6:43570920:C:A	K125N	0.999
6:43570920:C:G	K125N	0.999
6:43572569:C:A	W79C	0.999
6:43572569:C:G	W79C	0.999
6:43573504:A:G	L68P	0.999
6:43573507:C:T	G67D	0.999
6:43573555:C:T	G51D	0.999

dbSNP variants (sampled 300 via entrez): RS1000019455 (6:43543015 A>G), RS1000079109 (6:43549277 T>C), RS1000137217 (6:43531781 G>C), RS1000196583 (6:43540479 AAAATAAAT>A,AAAAT,AAAATAAATAAAT), RS1000217703 (6:43526651 G>A,C), RS1000286921 (6:43576248 G>A), RS1000314956 (6:43533184 C>A), RS1000351352 (6:43555337 C>T), RS1000392708 (6:43561486 C>A), RS1000423254 (6:43542311 C>A,T), RS1000468892 (6:43535216 C>G,T), RS1000501210 (6:43525493 C>T), RS1000553470 (6:43525188 T>G), RS1000735458 (6:43535407 T>A,C), RS1000742547 (6:43530507 T>G)

Disease associations

OMIM: gene MIM:607845 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome	Limited	Autosomal recessive

Mondo (1): nephrotic syndrome (MONDO:0005377)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005956_58	Waist-to-hip ratio adjusted for BMI	7.000000e-26
GCST005957_1	Waist-to-hip ratio adjusted for BMI (age <50)	2.000000e-14
GCST005958_2	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-19
GCST005962_2	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-31
GCST010083_46	Hemoglobin levels	1.000000e-09
GCST90002402_694	Platelet count	5.000000e-12

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004509	hemoglobin measurement
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724609 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs34324334	XPO5		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.32	Kd	47.5	nM	CHEMBL3752910
7.32	ED50	47.5	nM	CHEMBL3752910
5.43	Kd	3692	nM	CHEMBL5653589
5.43	ED50	3692	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149787: Binding affinity to human XPO5 incubated for 45 mins by Kinobead based pull down assay	kd	0.0475	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149787: Binding affinity to human XPO5 incubated for 45 mins by Kinobead based pull down assay	kd	3.6918	uM

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression, affects response to substance	3
bisphenol A	decreases reaction, increases expression, decreases expression, affects reaction	2
Calcitriol	decreases expression	2
Estradiol	increases expression	2
Lead	decreases expression, affects response to substance	2
Ozone	affects expression, affects cotreatment, increases expression, increases abundance	2
Tretinoin	decreases expression	2
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	1
4-phenylbutyric acid	decreases expression	1
perfluoro-n-nonanoic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	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
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	decreases reaction, increases expression	1
Bortezomib	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652829	Binding	Binding affinity to human XPO5 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7HT	Ubigene HEK293T XPO5 KO	Transformed cell line	Female
CVCL_KT54	HeLa SilenciX Exportin 5	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT00001212	PHASE2	COMPLETED	Drug Therapy in Lupus Nephropathy
NCT00001959	PHASE2	COMPLETED	Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
NCT00004466	PHASE2	TERMINATED	Pilot Study of Atorvastatin in Children With Chronic Hyperlipidemia Secondary to Nephrotic Syndrome
NCT00004990	PHASE2	COMPLETED	Once-A-Month Steroid Treatment for Patients With Focal Segmental Glomerulosclerosis
NCT00977977	PHASE2	RECRUITING	Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy
NCT02394106	PHASE2	TERMINATED	Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome
NCT02394119	PHASE2	COMPLETED	Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT02966717	PHASE2	UNKNOWN	Rituximab Combined With MSCs in the Treatment of PNS (3-4 Stage of CKD)
NCT03004001	PHASE2	TERMINATED	Effect of PCSK9-Antibody (Alirocumab) on Dyslipidemia Secondary to Nephrotic Syndrome
NCT03949855	PHASE2	RECRUITING	Belimumab With Rituximab for Primary Membranous Nephropathy
NCT05599815	PHASE2	WITHDRAWN	Part 1 - A Clinical Trial in Patients With Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome
NCT05704400	PHASE2	UNKNOWN	Efficacy of Anti-CD20 Ab Associated With Anti-CD38 in the Childhood Multidrug Dependent and Resistant Nephrotic Syndrome
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases