UPK3A

Summary

UPK3A (uroplakin 3A, HGNC:12580) is a protein-coding gene on chromosome 22q13.31, encoding Uroplakin-3a (O75631). Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells.

This gene encodes a member of the uroplakin family, a group of transmembrane proteins that form complexes on the apical surface of the bladder epithelium. Mutations in this gene may be associated with renal adysplasia. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 7380 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal agenesis, unilateral (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 100 total — 1 likely-pathogenic
• MANE Select transcript: NM_006953

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12580
Approved symbol	UPK3A
Name	uroplakin 3A
Location	22q13.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100373
Ensembl biotype	protein_coding
OMIM	611559
Entrez	7380

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000216211, ENST00000396082, ENST00000938588, ENST00000957030

RefSeq mRNA: 2 — MANE Select: NM_006953 NM_001167574, NM_006953

CCDS: CCDS14064, CCDS54539

Canonical transcript exons

ENST00000216211 — 6 exons

Exon	Start	End
ENSE00000657062	45287172	45287451
ENSE00000657064	45293181	45293313
ENSE00000880720	45284949	45285065
ENSE00000880721	45285941	45286096
ENSE00000880722	45295560	45295874
ENSE00001314037	45289061	45289143

Expression profiles

Bgee: expression breadth ubiquitous, 126 present calls, max score 83.14.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6820 / max 128.0077, expressed in 192 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192703	0.6399	180
192704	0.0242	13
192705	0.0179	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	83.14	gold quality
mucosa of urinary bladder	UBERON:0001259	82.50	gold quality
muscle of leg	UBERON:0001383	81.94	gold quality
monocyte	CL:0000576	81.25	gold quality
urinary bladder	UBERON:0001255	81.15	gold quality
mononuclear cell	CL:0000842	80.96	gold quality
leukocyte	CL:0000738	80.47	gold quality
prostate gland	UBERON:0002367	79.59	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.03	gold quality
muscle organ	UBERON:0001630	78.74	gold quality
triceps brachii	UBERON:0001509	77.45	gold quality
granulocyte	CL:0000094	74.35	gold quality
gluteal muscle	UBERON:0002000	72.19	gold quality
sperm	CL:0000019	71.57	gold quality
buccal mucosa cell	CL:0002336	71.49	gold quality
biceps brachii	UBERON:0001507	70.01	silver quality
male germ cell	CL:0000015	69.88	gold quality
skeletal muscle tissue	UBERON:0001134	68.17	gold quality
diaphragm	UBERON:0001103	65.50	gold quality
muscle tissue	UBERON:0002385	65.04	gold quality
deltoid	UBERON:0001476	64.91	silver quality
tendon of biceps brachii	UBERON:0008188	63.84	gold quality
left lobe of thyroid gland	UBERON:0001120	62.03	gold quality
tongue squamous epithelium	UBERON:0006919	61.56	gold quality
blood	UBERON:0000178	61.09	gold quality
endometrium epithelium	UBERON:0004811	61.09	gold quality
thyroid gland	UBERON:0002046	60.95	gold quality
right lobe of thyroid gland	UBERON:0001119	60.74	gold quality
gall bladder	UBERON:0002110	59.45	gold quality
cartilage tissue	UBERON:0002418	58.02	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	446.90
E-CURD-112	yes	13.83
E-ANND-3	yes	4.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARG

miRNA regulators (miRDB)

5 targeting UPK3A, 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-670-5P	99.67	69.94	1565
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-6515-5P	97.08	65.48	1219

Literature-anchored findings (GeneRIF, showing 13)

• Loss of p63 expression is a prerequisite for uroplakin III expression in urothelial bladder cancer. (PMID:14654529)
• Our results indicate that de novo mutations in UPIIIA can be involved in defective early kidney development, but probably constitute only a rare cause of human renal hypodysplasia in a minor subset of individuals [UPIIIA]. (PMID:16731295)
• uroplakin III and III-delta4 genes were significantly up-regulated only in patients with nonulcerative interstitial cystitis (PMID:17698128)
• Uroplakin III mRNA is up-regulated to a greater extent in vesicoureteral reflux than in control exfoliated urinary cells. (PMID:17880289)
• Loss of UP III expression is associated with established markers of biologically aggressive bladder cancer (PMID:18313120)
• Not a useful immunohistochemical marker for detection of pleural malignant mesothelioma. (PMID:18528285)
• Uroplakin III plays a pivotal role in Eshcerichia coli UTI pathogenesis. (PMID:19007907)
• studies suggest that bacteria-induced UPIIIa signaling is a critical mediator of bladder responses to insult by uropathogenic E. coli (PMID:19412341)
• a strong association between UPIII and in the group with tumor recurrence (PMID:24553301)
• High Uroplakin III expression is associated with bladder urothelial carcinoma from malignancy metastatic to the urinary bladder. (PMID:25368291)
• High expression level of preoperative serum Uroplakin III is associated with biologically aggressive bladder cancer. (PMID:25743828)
• UPIIIa is a biomarker for bladder cancer that is unrelated to chemical carcinogenesis (PMID:30069482)
• High Expression of UPK3A Promotes the Progression of Gastric Cancer Cells by Inactivating p53 Pathway. (PMID:35774082)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Upk3a	ENSMUSG00000022435
rattus_norvegicus	Upk3a	ENSRNOG00000013593

Paralogs (3): UPK3B (ENSG00000243566), UPK3BL1 (ENSG00000267368), UPK3BL2 (ENSG00000284981)

Protein

Protein identifiers

Uroplakin-3a — O75631 (reviewed: O75631)

Alternative names: Uroplakin III

All UniProt accessions (1): O75631

UniProt curated annotations — full annotation on UniProt →

Function. Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in AUM-cytoskeleton interaction in terminally differentiated urothelial cells. It also contributes to the formation of urothelial glycocalyx which may play an important role in preventing bacterial adherence.

Subunit / interactions. Heterodimer with uroplakin-1B (UPK1B).

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in ureter.

Disease relevance. Mutations in UPK3A have been detected in patients with renal adyplasia suggesting a possible involvement of this gene in kidney and urinary tract anomalies.

Similarity. Belongs to the uroplakin-3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75631-1	1	yes
O75631-2	2

RefSeq proteins (2): NP_001161046, NP_008884* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024825	Uroplakin-3a	Family
IPR024831	Uroplakin-3	Family

UniProt features (16 total): sequence variant 4, glycosylation site 3, topological domain 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75631-F1	78.77	0.49

Functional residue map

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

Glycosylation sites (3): 74, 139, 170

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 92 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POTASSIUM_ION_HOMEOSTASIS, CHANDRAN_METASTASIS_DN, HOFMANN_MYELODYSPLASTIC_SYNDROM_RISK_DN, GOBP_WATER_TRANSPORT, GOBP_ONE_CARBON_COMPOUND_TRANSPORT, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_SODIUM_ION_HOMEOSTASIS, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_MONOATOMIC_ION_HOMEOSTASIS, OCT1_B, P53_DECAMER_Q2, GOBP_FLUID_TRANSPORT, GOCC_APICAL_PART_OF_CELL

GO Biological Process (8): cell morphogenesis (GO:0000902), kidney development (GO:0001822), water transport (GO:0006833), urea transport (GO:0015840), epithelial cell differentiation (GO:0030855), potassium ion homeostasis (GO:0055075), sodium ion homeostasis (GO:0055078), urinary bladder development (GO:0060157)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (7): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), apical plasma membrane urothelial plaque (GO:0120001), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), apical plasma membrane (GO:0016324)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	2
renal system development	2
monoatomic cation homeostasis	2
inorganic ion homeostasis	2
plasma membrane region	2
anatomical structure morphogenesis	1
fluid transport	1
one-carbon compound transport	1
nitrogen compound transport	1
cell differentiation	1
epithelium development	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
extracellular vesicle	1
plasma membrane	1
apical plasma membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
apical part of cell	1

Protein interactions and networks

STRING

498 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UPK3A	UPK1A	O00322	999
UPK3A	UPK2	O00526	999
UPK3A	UPK1B	O75841	999
UPK3A	KRT20	P35900	728
UPK3A	CD151	P48509	663
UPK3A	LIAT1	Q6ZQX7	654
UPK3A	CD53	P19397	649
UPK3A	CD37	P11049	633
UPK3A	KRT7	P08729	621
UPK3A	KRT5	P13647	583
UPK3A	CD63	P08962	555
UPK3A	KRT14	P02533	507
UPK3A	HOXA9	P31269	478
UPK3A	TMEM14A	Q9Y6G1	469
UPK3A	RET	P07949	466

IntAct

7 interactions, top by confidence:

A	B	Type	Score
UPK3A	SGTA	psi-mi:“MI:0915”(physical association)	0.560
SGTA	UPK3A	psi-mi:“MI:0915”(physical association)	0.560
UPK3A	SGTB	psi-mi:“MI:0915”(physical association)	0.560
UPK3A	SGTB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): UPK3A (Two-hybrid), SGTB (Two-hybrid), UPK1B (Affinity Capture-Western)

ESM2 similar proteins: A5PJ93, A6NH21, A6QQ85, A8MVS5, B0FP48, E5RIL1, E9PY61, O75631, P0C6B2, P38574, P42701, P57785, Q08351, Q15904, Q561R0, Q5T7M4, Q63148, Q64280, Q6AZ51, Q6IEE6, Q6PRD1, Q6ZVW7, Q75VT8, Q7TN60, Q80YF6, Q864V4, Q867C0, Q8BH06, Q8BX43, Q8CHT6, Q8CJ26, Q8IZI9, Q8IZJ0, Q8K4C2, Q8K5A9, Q8N3T6, Q8N9H8, Q8NAC3, Q8NFR9, Q8R2Z0

Diamond homologs: O75631, P38574, Q80YF6, Q864V4, Q9JKX8, A6QQ85, B0FP48, E5RIL1, Q13670, Q9BT76, Q9D701

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	63
Likely benign	10
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
191171	NM_006953.4(UPK3A):c.53-1G>A	Likely pathogenic

SpliceAI

1025 predictions. Top by Δscore:

Variant	Effect	Δscore
22:45286093:TCAGG:T	donor_loss	1.0000
22:45286094:CAGG:C	donor_loss	1.0000
22:45286095:AGGT:A	donor_loss	1.0000
22:45286097:G:C	donor_loss	1.0000
22:45286098:T:G	donor_loss	1.0000
22:45289142:GC:G	donor_gain	1.0000
22:45289144:G:GG	donor_gain	1.0000
22:45293179:A:AG	acceptor_gain	1.0000
22:45293180:G:GA	acceptor_gain	1.0000
22:45286097:G:GG	donor_gain	0.9900
22:45293180:GT:G	acceptor_gain	0.9900
22:45293180:GTC:G	acceptor_gain	0.9900
22:45293312:GT:G	donor_gain	0.9900
22:45285193:A:AG	donor_gain	0.9800
22:45289141:AGC:A	donor_gain	0.9800
22:45289141:AGCG:A	donor_loss	0.9800
22:45289142:GCG:G	donor_gain	0.9800
22:45289142:GCGTA:G	donor_loss	0.9800
22:45289143:CGTA:C	donor_loss	0.9800
22:45289144:G:GC	donor_loss	0.9800
22:45289145:T:G	donor_loss	0.9800
22:45289146:A:AT	donor_loss	0.9800
22:45289147:AG:A	donor_loss	0.9800
22:45289148:G:A	donor_loss	0.9800
22:45293180:GTCA:G	acceptor_gain	0.9800
22:45293180:GTCAC:G	acceptor_gain	0.9800
22:45288835:G:GT	donor_gain	0.9700
22:45289139:CCAGC:C	donor_gain	0.9700
22:45293314:G:GG	donor_gain	0.9700
22:45285936:TCCAG:T	acceptor_gain	0.9600

AlphaMissense

1836 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:45289118:G:C	W182C	0.993
22:45289118:G:T	W182C	0.993
22:45289116:T:A	W182R	0.991
22:45289116:T:C	W182R	0.991
22:45287417:T:A	C152S	0.982
22:45287418:G:C	C152S	0.982
22:45286013:T:C	L42S	0.981
22:45286034:T:G	F49C	0.981
22:45293238:T:A	V210D	0.981
22:45287447:T:G	Y162D	0.980
22:45289063:T:C	F164S	0.980
22:45289068:T:G	Y166D	0.978
22:45289119:T:C	S183P	0.978
22:45287372:G:T	G137C	0.976
22:45289062:T:C	F164L	0.975
22:45289064:C:A	F164L	0.975
22:45289064:C:G	F164L	0.975
22:45289069:A:C	Y166S	0.975
22:45287447:T:C	Y162H	0.972
22:45286027:T:A	C47S	0.971
22:45286028:G:C	C47S	0.971
22:45289068:T:C	Y166H	0.970
22:45287261:T:G	Y100D	0.969
22:45287373:G:T	G137V	0.969
22:45289069:A:G	Y166C	0.968
22:45287387:T:C	C142R	0.967
22:45287417:T:C	C152R	0.967
22:45287418:G:A	C152Y	0.967
22:45285956:C:A	P23H	0.965
22:45285990:C:A	N34K	0.964

dbSNP variants (sampled 300 via entrez): RS1000534408 (22:45286570 G>T), RS1000763837 (22:45290917 G>A), RS1000832830 (22:45291894 G>A,C), RS1000966953 (22:45295481 A>G), RS1001063731 (22:45293927 G>A), RS1001262466 (22:45288700 A>G), RS1002065518 (22:45292767 G>C,T), RS1002306058 (22:45293107 C>A,T), RS1002324890 (22:45283277 A>G,T), RS1002336213 (22:45283030 C>T), RS1002657378 (22:45287901 T>A), RS1002908401 (22:45285700 C>T), RS1003259984 (22:45291940 G>A), RS1003307707 (22:45291681 G>A), RS1003329255 (22:45290734 T>A,G)

Disease associations

OMIM: gene MIM:611559 | disease phenotypes: MIM:191830, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
renal agenesis, unilateral	Supportive	Autosomal dominant
renal dysplasia	Limited	Autosomal dominant
congenital anomaly of kidney and urinary tract	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital anomaly of kidney and urinary tract	Disputed	AD

Mondo (5): renal hypodysplasia/aplasia 1 (MONDO:0024519), congenital anomalies of kidney and urinary tract 1 (MONDO:0012561), renal dysplasia (MONDO:0019638), congenital anomaly of kidney and urinary tract (MONDO:0019719), renal agenesis, unilateral (MONDO:0019636)

Orphanet (1): Renal agenesis (Orphanet:411709)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001918_1	Pulmonary function in asthmatics	4.000000e-07
GCST008839_269	Height	3.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)
C563661	Renal Hypodysplasia, Nonsyndromic, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	3
Cyclosporine	decreases expression	3
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
Capecitabine	increases expression	1
Estradiol	decreases expression	1
Quercetin	decreases expression	1
Tamoxifen	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	affects expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02021006	PHASE3	UNKNOWN	Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
NCT01831141	Not specified	UNKNOWN	Long Term Outcome of Congenital Solitary Kidney
NCT00925379	Not specified	COMPLETED	Renal HYPODYSPLASIA : Genetic and Familial Assessment