GUCA2B

Summary

GUCA2B (guanylate cyclase activator 2B, HGNC:4683) is a protein-coding gene on chromosome 1p34.2, encoding Guanylate cyclase activator 2B (Q16661). Endogenous activator of intestinal guanylate cyclase.

This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products, including uroguanylin, a member of the guanylin family of peptides and an endogenous ligand of the guanylate cyclase-C receptor. Binding of this peptide to its cognate receptor stimulates an increase in cyclic GMP and may regulate salt and water homeostasis in the intestine and kidneys.

Source: NCBI Gene 2981 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 14 total
• MANE Select transcript: NM_007102

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4683
Approved symbol	GUCA2B
Name	guanylate cyclase activator 2B
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000044012
Ensembl biotype	protein_coding
OMIM	601271
Entrez	2981

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000372581

RefSeq mRNA: 1 — MANE Select: NM_007102 NM_007102

CCDS: CCDS464

Canonical transcript exons

ENST00000372581 — 3 exons

Exon	Start	End
ENSE00000768944	42154680	42154866
ENSE00000870150	42155535	42155820
ENSE00001458144	42153410	42153540

Expression profiles

Bgee: expression breadth broad, 76 present calls, max score 98.58.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2693 / max 267.1939, expressed in 15 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2445	0.2596	13
2446	0.0096	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	98.58	gold quality
mucosa of transverse colon	UBERON:0004991	97.54	gold quality
colonic mucosa	UBERON:0000317	95.01	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.83	gold quality
jejunal mucosa	UBERON:0000399	93.81	gold quality
duodenum	UBERON:0002114	88.57	gold quality
rectum	UBERON:0001052	87.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.00	gold quality
transverse colon	UBERON:0001157	85.92	gold quality
small intestine	UBERON:0002108	85.48	gold quality
intestine	UBERON:0000160	76.68	gold quality
large intestine	UBERON:0000059	74.44	gold quality
colon	UBERON:0001155	73.85	gold quality
jejunum	UBERON:0002115	69.96	gold quality
right lobe of liver	UBERON:0001114	68.06	gold quality
body of stomach	UBERON:0001161	66.56	gold quality
endometrium epithelium	UBERON:0004811	66.19	gold quality
colonic epithelium	UBERON:0000397	64.08	gold quality
esophagus squamous epithelium	UBERON:0006920	61.50	gold quality
stomach	UBERON:0000945	61.22	gold quality
liver	UBERON:0002107	61.01	gold quality
oocyte	CL:0000023	60.92	gold quality
epithelium of esophagus	UBERON:0001976	60.17	gold quality
sigmoid colon	UBERON:0001159	58.32	gold quality
secondary oocyte	CL:0000655	57.83	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.13	gold quality
tendon of biceps brachii	UBERON:0008188	56.26	gold quality
parotid gland	UBERON:0001831	56.23	gold quality
squamous epithelium	UBERON:0006914	55.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	9.79
E-ANND-3	yes	4.20

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HSF1

miRNA regulators (miRDB)

12 targeting GUCA2B, 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-4492	99.87	68.25	3611
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-3620-5P	97.42	63.95	792
HSA-MIR-1587	96.95	64.03	932
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280

Literature-anchored findings (GeneRIF, showing 11)

• Uroguanylin concentrations are increased in patients with chronic renal failure, nephrotic syndrome, or those on dialysis. (PMID:15780094)
• The occurrences of the C-A haplotype (rs883062-rs1047047) and the C-A-G haplotype (rs883062-rs1047047-rs2297566) were significantly higher in the essential hypertension group than in the controls. (PMID:18037771)
• The specific cellular distribution of both GN and UGN differs between duodenum and colon and between human and rat intestines. (PMID:27044258)
• Both guanylin and uroguanylin trigger lipolysis in human visceral adipocytes. Given the lipolytic action of the guanylin system on visceral adipocytes, the herein reported decrease of circulating prouroguanylin concentrations in obese patients may have a role in excessive fat accumulation in obesity. (PMID:27108812)
• Results demonstrate that GC-C and its ligands, guanylin and uroguanylin are downregulated in ulcerative colitis (UC), and this downregulation is more significant with aggravation of the clinical condition. Therefore, the GC-C signaling pathway may be implicated in the progression of UC. (PMID:27125248)
• The simulations suggested that all missense SNPs considered as convergent deleterious caused some kind of structural change to the uroguanylin peptide. Additionally, four of these SNPs were also shown to cause modifications in peptide flexibility, possibly resulting in functional changes. (PMID:27620667)
• The intestinal expression of uroguanylin, a key satiety hormone, appears to be diminished in female pediatric patients in the setting of obesity. (PMID:28847213)
• In female adolescents without obesity, levels of pro-uroguanylin are higher than in those with obesity. Pro-uroguanylin secretion patterns differ from other circulating gastrointestinal peptides. In female adolescents with obesity, inflammation correlates with decreased pro-uroguanylin levels. (PMID:29112082)
• Guanylin and uroguanylin, as well as their prohormones, do not seem to play a significant role in body weight regulation and glycemic control, suggesting that guanylin-family peptides do not show promise as targets for the treatment of obesity or diabetes. (PMID:29289697)
• This study investigates pro-uroguanylin circulating levels in children with obesity and its relationship with obesity, sex and pubertal development. Sexual dimorphism exists in circulating pro-uroguanylin levels with respect to Body Mass Index. (PMID:30266914)
• High plasma and lingual uroguanylin as potential contributors to changes in food preference after sleeve gastrectomy. (PMID:34990711)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Guca2b	ENSMUSG00000032978
rattus_norvegicus	Guca2b	ENSRNOG00000008979

Paralogs (1): GUCA2A (ENSG00000197273)

Protein

Protein identifiers

Guanylate cyclase activator 2B — Q16661 (reviewed: Q16661)

All UniProt accessions (1): Q16661

UniProt curated annotations — full annotation on UniProt →

Function. Endogenous activator of intestinal guanylate cyclase. It stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins. May be a potent physiological regulator of intestinal fluid and electrolyte transport. May be an autocrine/paracrine regulator of intestinal salt and water transport.

Subcellular location. Secreted.

Tissue specificity. Stomach and intestine.

Similarity. Belongs to the guanylin family.

RefSeq proteins (1): NP_009033* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000879	Guanylin	Family
IPR036382	Guanylin_sf	Homologous_superfamily

Pfam: PF02058

UniProt features (9 total): disulfide bond 3, peptide 2, signal peptide 1, propeptide 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1UYA	SOLUTION NMR
1UYB	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16661-F1	83.26	0.39

Functional residue map

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

Disulfide bonds (3): 67–80, 100–108, 103–111

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8935690	Digestion

MSigDB gene sets: 96 (showing top): MODULE_416, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_DIETARY_EXCESS, GOBP_GROWTH, HNF1_Q6, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_EATING_BEHAVIOR, chr1p34, GOBP_MULTICELLULAR_ORGANISM_GROWTH, RYTAAWNNNTGAY_UNKNOWN, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_SECRETION

GO Biological Process (10): reduction of food intake in response to dietary excess (GO:0002023), body fluid secretion (GO:0007589), response to glucose (GO:0009749), obsolete cGMP-mediated signaling (GO:0019934), multicellular organism growth (GO:0035264), glucose homeostasis (GO:0042593), negative regulation of blood pressure (GO:0045776), adipose tissue development (GO:0060612), renal sodium ion absorption (GO:0070294), energy homeostasis (GO:0097009)

GO Molecular Function (2): guanylate cyclase activator activity (GO:0030250), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Digestion and absorption	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to dietary excess	1
eating behavior	1
secretion	1
regulation of body fluid levels	1
response to hexose	1
multicellular organismal process	1
developmental growth	1
carbohydrate homeostasis	1
regulation of blood pressure	1
animal organ development	1
connective tissue development	1
renal sodium ion transport	1
renal absorption	1
multicellular organismal-level homeostasis	1
guanylate cyclase activity	1
cyclase activator activity	1
guanylate cyclase regulator activity	1
binding	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCA2B	GUCY2C	P25092	999
GUCA2B	NPR3	P17342	996
GUCA2B	EMD	P50402	968
GUCA2B	CFTR	P13569	764
GUCA2B	GUCA1B	Q9UMX6	713
GUCA2B	GUCY2D	Q02846	682
GUCA2B	NPPA	P01160	660
GUCA2B	GCDH	Q92947	646
GUCA2B	MS4A12	Q9NXJ0	621
GUCA2B	GCC1	Q96CN9	591
GUCA2B	PRKG2	Q13237	585
GUCA2B	SLC9A3	P48764	582
GUCA2B	NPR2	P20594	577
GUCA2B	NHERF4	Q86UT5	568
GUCA2B	NPPB	P16860	564

IntAct

8 interactions, top by confidence:

A	B	Type	Score
GUCA2B	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
GUCA2B	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
GUCA2B	PYY	psi-mi:“MI:0915”(physical association)	0.400
GUCA2B	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
UBQLN1	GUCA2B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): UBQLN1 (Two-hybrid), UBQLN2 (Two-hybrid), PYY (Affinity Capture-MS)

ESM2 similar proteins: A0A8M9PDM1, A0JNP2, O09051, O75556, O95968, O95969, P02779, P02780, P02781, P02782, P04769, P06913, P09320, P0DMR2, P11684, P17559, P28902, P30438, P30440, P33578, P33579, P33580, P33680, P70664, P70668, P79897, Q02747, Q05702, Q06318, Q0PGP2, Q13296, Q16661, Q28358, Q2VPS3, Q4G0G5, Q6UGQ3, Q6XE38, Q7M742, Q7M747, Q8CGZ9

Diamond homologs: O09051, O13009, P70107, P70664, P70668, Q02747, Q16661, Q28358, Q8R5G8, P79897, P28902, P33680, Q8R5G9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GUCA2B	up-regulates	GUCY2C	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

324 predictions. Top by Δscore:

Variant	Effect	Δscore
1:42153541:G:GG	donor_gain	1.0000
1:42153541:GT:G	donor_loss	1.0000
1:42154671:T:TA	acceptor_gain	1.0000
1:42154675:T:A	acceptor_gain	1.0000
1:42154675:TGTA:T	acceptor_gain	1.0000
1:42154675:TGTAG:T	acceptor_loss	1.0000
1:42154676:GTAG:G	acceptor_gain	1.0000
1:42154676:GTAGT:G	acceptor_loss	1.0000
1:42154677:TAG:T	acceptor_loss	1.0000
1:42154677:TAGT:T	acceptor_gain	1.0000
1:42154678:A:AG	acceptor_gain	1.0000
1:42154678:AGT:A	acceptor_loss	1.0000
1:42154678:AGTA:A	acceptor_gain	1.0000
1:42154679:G:GA	acceptor_gain	1.0000
1:42154679:GT:G	acceptor_gain	1.0000
1:42154679:GTA:G	acceptor_gain	1.0000
1:42154679:GTAC:G	acceptor_gain	1.0000
1:42154679:GTACC:G	acceptor_gain	1.0000
1:42154865:GA:G	donor_gain	1.0000
1:42154867:G:GG	donor_gain	1.0000
1:42153536:TCCAG:T	donor_gain	0.9900
1:42153538:CAG:C	donor_gain	0.9900
1:42154671:T:A	acceptor_loss	0.9900
1:42154674:CTGTA:C	acceptor_gain	0.9900
1:42154679:G:A	acceptor_gain	0.9900
1:42154862:CCTGA:C	donor_gain	0.9900
1:42154863:CTGA:C	donor_gain	0.9900
1:42154864:TGA:T	donor_gain	0.9900
1:42154865:GAG:G	donor_gain	0.9900
1:42154865:GAGT:G	donor_loss	0.9900

AlphaMissense

710 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:42154827:T:A	C80S	0.883
1:42154828:G:C	C80S	0.883
1:42154696:T:A	V36D	0.877
1:42154825:T:A	V79D	0.875
1:42154689:T:C	F34L	0.869
1:42154691:C:A	F34L	0.869
1:42154691:C:G	F34L	0.869
1:42154816:T:C	L76P	0.868
1:42154788:T:A	C67S	0.867
1:42154789:G:C	C67S	0.867
1:42155564:T:A	C103S	0.867
1:42155565:G:C	C103S	0.867
1:42155585:G:T	G110C	0.858
1:42154788:T:C	C67R	0.839
1:42154827:T:C	C80R	0.837
1:42153536:T:C	I29T	0.836
1:42155588:T:C	C111R	0.831
1:42154828:G:A	C80Y	0.830
1:42155571:A:T	N105I	0.819
1:42155564:T:C	C103R	0.817
1:42155572:C:A	N105K	0.817
1:42155572:C:G	N105K	0.817
1:42154816:T:A	L76H	0.816
1:42155565:G:A	C103Y	0.815
1:42155579:T:A	C108S	0.814
1:42155580:G:C	C108S	0.814
1:42155588:T:A	C111S	0.810
1:42155589:G:C	C111S	0.810
1:42154829:C:G	C80W	0.798
1:42155580:G:A	C108Y	0.795

dbSNP variants (sampled 300 via entrez): RS1000176421 (1:42153328 A>C,T), RS1001483983 (1:42153833 G>T), RS1001817606 (1:42154956 G>A), RS1001844618 (1:42156204 T>C), RS1002051147 (1:42151705 C>T), RS1002420379 (1:42151472 C>A,T), RS1002755191 (1:42156139 A>G), RS1004362088 (1:42154982 C>G), RS1005027566 (1:42155093 C>T), RS1005273202 (1:42154995 C>G), RS1005624402 (1:42154099 C>A,T), RS1005776729 (1:42153778 G>T), RS1006365602 (1:42152817 G>A), RS1006810044 (1:42153076 G>A), RS1006957847 (1:42153362 G>A,C)

Disease associations

OMIM: gene MIM:601271 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010241_245	Apolipoprotein A1 levels	4.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1

Clinical trials (associated diseases)

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