GPHB5

Summary

GPHB5 (glycoprotein hormone subunit beta 5, HGNC:18055) is a protein-coding gene on chromosome 14q23.2, encoding Glycoprotein hormone beta-5 (Q86YW7). Functions as a heterodimeric glycoprotein hormone with GPHA2 able to bind and activate the thyroid-stimulating hormone receptor (TSHR), leading to increased cAMP production.

GPHB5 is a cystine knot-forming polypeptide and a subunit of the dimeric glycoprotein hormone family (Hsu et al., 2002 [PubMed 12089349]).

Source: NCBI Gene 122876 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 6 total
• MANE Select transcript: NM_145171

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18055
Approved symbol	GPHB5
Name	glycoprotein hormone subunit beta 5
Location	14q23.2
Locus type	gene with protein product
Status	Approved
Aliases	ZLUT1, GPB5
Ensembl gene	ENSG00000179600
Ensembl biotype	protein_coding
OMIM	609652
Entrez	122876

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000314140, ENST00000621500

RefSeq mRNA: 1 — MANE Select: NM_145171 NM_145171

CCDS: CCDS73643

Canonical transcript exons

ENST00000621500 — 3 exons

Exon	Start	End
ENSE00001233041	63317646	63317850
ENSE00003716020	63312835	63313116
ENSE00003721033	63318824	63318935

Expression profiles

Bgee: expression breadth broad, 29 present calls, max score 92.34.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0027 / max 2.0644, expressed in 2 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143590	0.0027	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.34	gold quality
oocyte	CL:0000023	59.63	gold quality
skin of hip	UBERON:0001554	56.74	silver quality
myocardium	UBERON:0002349	55.91	gold quality
sperm	CL:0000019	54.00	gold quality
trabecular bone tissue	UBERON:0002483	53.54	gold quality
parotid gland	UBERON:0001831	52.64	gold quality
upper leg skin	UBERON:0004262	46.90	silver quality
tendon of biceps brachii	UBERON:0008188	46.76	gold quality
vastus lateralis	UBERON:0001379	44.20	gold quality
amniotic fluid	UBERON:0000173	44.15	gold quality
quadriceps femoris	UBERON:0001377	44.10	gold quality
substantia nigra pars compacta	UBERON:0001965	43.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	41.63	silver quality
middle temporal gyrus	UBERON:0002771	41.48	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
oviduct epithelium	UBERON:0004804	41.03	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
ventral tegmental area	UBERON:0002691	40.93	gold quality
cerebellar hemisphere	UBERON:0002245	40.73	silver quality
medial globus pallidus	UBERON:0002477	40.66	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
cerebellar cortex	UBERON:0002129	40.47	silver quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
globus pallidus	UBERON:0001875	40.34	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.79

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, RELA

Literature-anchored findings (GeneRIF, showing 7)

• Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor (thyrostimulin) (PMID:12045258)
• identification and characterization of GPB5 genes (PMID:12089349)
• Srosophila GPA2/GPB5 heterodimers did not activate human TSH or gonadotropin receptors, chimeric fly GPA2/human GPB5 heterodimers stimulated human TSH receptors. (GPA2 in drosophila) (PMID:15890769)
• Dual site-disrupted GPA2 and the GPB5 mutant were not expressed in either the conditioned medium or cell lysate. (PMID:18433898)
• Inflammatory cytokines positively regulate thyrostimulin through NF-kappaB activation. (PMID:19095738)
• GPHB5 Is a Biomarker in Women With Metabolic Syndrome: Results From Cross-Sectional and Intervention Studies. (PMID:35757403)
• Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies. (PMID:36568071)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gphb5	ENSDARG00000027472
mus_musculus	Gphb5	ENSMUSG00000048982
rattus_norvegicus	Gphb5	ENSRNOG00000083703
drosophila_melanogaster	Gpb5	FBGN0063368

Paralogs (9): CGB2 (ENSG00000104818), LHB (ENSG00000104826), CGB3 (ENSG00000104827), FSHB (ENSG00000131808), TSHB (ENSG00000134200), CGB5 (ENSG00000189052), CGB7 (ENSG00000196337), CGB8 (ENSG00000213030), CGB1 (ENSG00000267631)

Protein

Protein identifiers

Glycoprotein hormone beta-5 — Q86YW7 (reviewed: Q86YW7)

Alternative names: Thyrostimulin subunit beta

All UniProt accessions (2): A0A0F7RPU1, Q86YW7

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a heterodimeric glycoprotein hormone with GPHA2 able to bind and activate the thyroid-stimulating hormone receptor (TSHR), leading to increased cAMP production. Plays a central role in controlling thyroid cell metabolism.

Subunit / interactions. Heterodimer with GPHA2; this heterodimer interacts with thyroid-stimulating hormone receptor (TSHR), and hence stimulates cAMP production.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in brain and at low levels in pituitary. Also found in retina, testis and skin but not in pancreas, parotid, kidney, stomach, liver, colon, small intestine, thyroid, brain or adrenal gland. In pituitary, colocalizes with ACTH, suggesting that it is located in corticotrophs.

Post-translational modifications. N-glycosylated.

Similarity. Belongs to the glycoprotein hormones subunit beta family.

RefSeq proteins (1): NP_660154* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001545	Gonadotropin_bsu	Family
IPR006208	Glyco_hormone_CN	Domain
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00007

UniProt features (10 total): disulfide bond 5, sequence conflict 2, signal peptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86YW7-F1	87.84	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.

Disulfide bonds (5): 36–84, 50–99, 60–115, 64–117, 120–127

Glycosylation sites (1): 87

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 47 (showing top): GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, REACTOME_HORMONE_LIGAND_BINDING_RECEPTORS, GOBP_RESPONSE_TO_HORMONE, AACTTT_UNKNOWN, GOBP_INTRACELLULAR_RECEPTOR_SIGNALING_PATHWAY, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, chr14q23, GOMF_SIGNALING_RECEPTOR_BINDING, ISRE_01, YNGTTNNNATT_UNKNOWN, TGGAAA_NFAT_Q4_01, GOBP_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, WGTTNNNNNAAA_UNKNOWN

GO Biological Process (4): regulation of thyroid hormone receptor signaling pathway (GO:0002155), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), signal transduction (GO:0007165)

GO Molecular Function (5): hormone activity (GO:0005179), thyrotropin-releasing hormone receptor binding (GO:0031531), protein heterodimerization activity (GO:0046982), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
thyroid hormone receptor signaling pathway	1
regulation of intracellular signal transduction	1
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
G protein-coupled receptor binding	1
peptide hormone receptor binding	1
protein dimerization activity	1
protein binding	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

366 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPHB5	GPHA2	Q96T91	997
GPHB5	CGA	P01215	886
GPHB5	FSHR	P23945	819
GPHB5	LHCGR	P22888	654
GPHB5	CMKLR2	P46091	582
GPHB5	TSHR	P16473	561
GPHB5	PPP2R5B	Q15173	547
GPHB5	TMEM254	Q8TBM7	522
GPHB5	PRL	P01236	440
GPHB5	OR4D9	Q8NGE8	439
GPHB5	GPHRA	B7ZAQ6	421
GPHB5	POMC	P01189	400
GPHB5	GYPB	P06028	399
GPHB5	GNRH1	P01148	380
GPHB5	GBP5	Q96PP8	374

IntAct

26 interactions, top by confidence:

A	B	Type	Score
GPHB5	GPHA2	psi-mi:“MI:0915”(physical association)	0.580
GPHB5	TMEM179B	psi-mi:“MI:0915”(physical association)	0.560
GPHB5	TEX29	psi-mi:“MI:0915”(physical association)	0.560
TMEM179B	GPHB5	psi-mi:“MI:0915”(physical association)	0.560
GPHB5	SSMEM1	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	GPHB5	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	GPHB5	psi-mi:“MI:0915”(physical association)	0.560
CIMIP2B	GPHB5	psi-mi:“MI:0915”(physical association)	0.560
ERVFRD-1	GPHB5	psi-mi:“MI:0915”(physical association)	0.560
ngl	GPHB5	psi-mi:“MI:2280”(deamidation reaction)	0.440
GPHB5	SSMEM1	psi-mi:“MI:0915”(physical association)	0.000
GPHB5	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.000
TMBIM6	GPHB5	psi-mi:“MI:0915”(physical association)	0.000
GPHB5	CIMIP2B	psi-mi:“MI:0915”(physical association)	0.000
GPHB5	ERVFRD-1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (6): GPHB5 (Two-hybrid), GPHB5 (Two-hybrid), GPHB5 (Two-hybrid), KRTAP10-8 (Two-hybrid), FAM166B (Two-hybrid), ERVFRD-1 (Two-hybrid)

ESM2 similar proteins: A9QWQ1, O14625, O18739, O46675, O46676, O46677, O46678, O97919, P08317, P09340, P09341, P10147, P10855, P10889, P12850, P13236, P13501, P14095, P14097, P16619, P19875, P19876, P28686, P30782, P30882, P41694, P42642, P46632, P47854, P50229, P50230, P50231, P97272, Q17QA1, Q53S33, Q5EBF6, Q5I1Z0, Q68A92, Q68AZ0, Q711P4

Diamond homologs: A1BN60, A1BN61, A6NKQ9, O09108, O13050, O46482, O46483, O46641, O57340, O73824, O77805, O77835, P01222, P01223, P01224, P01225, P01226, P01227, P01228, P01229, P01230, P01231, P01232, P01235, P04651, P04652, P04837, P07434, P07732, P08751, P0DN86, P0DN87, P10256, P12656, P12837, P18427, P18842, P19794, P25330, P27767

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

443 predictions. Top by Δscore:

Variant	Effect	Δscore
14:63313122:CCCA:C	acceptor_gain	1.0000
14:63313123:CCA:C	acceptor_gain	1.0000
14:63313124:C:T	acceptor_gain	1.0000
14:63313124:CA:C	acceptor_gain	1.0000
14:63313125:A:AC	acceptor_gain	1.0000
14:63313125:A:C	acceptor_gain	1.0000
14:63313114:TTTCT:T	acceptor_loss	0.9900
14:63313115:TT:T	acceptor_gain	0.9900
14:63313115:TTC:T	acceptor_loss	0.9900
14:63313117:C:CC	acceptor_gain	0.9900
14:63313121:CCCCA:C	acceptor_gain	0.9900
14:63313125:A:T	acceptor_gain	0.9900
14:63313129:A:C	acceptor_gain	0.9900
14:63317860:C:CT	acceptor_gain	0.9900
14:63317860:C:T	acceptor_gain	0.9900
14:63317861:G:T	acceptor_gain	0.9900
14:63318819:CTTA:C	donor_loss	0.9900
14:63318820:TTA:T	donor_loss	0.9900
14:63318821:TACC:T	donor_loss	0.9900
14:63313112:GGTTT:G	acceptor_gain	0.9800
14:63313113:GTTT:G	acceptor_gain	0.9800
14:63313114:TTT:T	acceptor_gain	0.9800
14:63313118:T:G	acceptor_loss	0.9800
14:63313129:A:AC	acceptor_gain	0.9800
14:63317851:CTGCT:C	acceptor_gain	0.9700
14:63318818:ACTT:A	donor_loss	0.9700
14:63318822:A:AC	donor_gain	0.9700
14:63318823:C:CC	donor_gain	0.9700
14:63317638:CAACT:C	donor_loss	0.9500
14:63317639:AACTC:A	donor_loss	0.9500

AlphaMissense

831 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:63317659:C:G	C64S	0.995
14:63317660:A:T	C64S	0.995
14:63317671:C:G	C60S	0.994
14:63317672:A:T	C60S	0.994
14:63317727:A:C	F41L	0.994
14:63317727:A:T	F41L	0.994
14:63317729:A:G	F41L	0.994
14:63313070:C:G	C84S	0.993
14:63313071:A:T	C84S	0.993
14:63317659:C:T	C64Y	0.993
14:63317666:C:A	G62C	0.993
14:63317670:G:C	C60W	0.993
14:63317671:C:T	C60Y	0.993
14:63312977:C:G	C115S	0.992
14:63312978:A:T	C115S	0.992
14:63313070:C:T	C84Y	0.992
14:63313071:A:G	C84R	0.992
14:63317659:C:A	C64F	0.992
14:63313069:A:C	C84W	0.991
14:63317672:A:G	C60R	0.991
14:63317743:C:G	C36S	0.991
14:63317744:A:T	C36S	0.991
14:63312996:A:C	Y109D	0.990
14:63317660:A:G	C64R	0.990
14:63317662:C:G	R63P	0.990
14:63317667:C:A	W61C	0.990
14:63317667:C:G	W61C	0.990
14:63312977:C:T	C115Y	0.989
14:63312978:A:G	C115R	0.989
14:63312986:G:T	A112D	0.989

dbSNP variants (sampled 300 via entrez): RS1000059886 (14:63320710 A>C,G), RS1000237137 (14:63314417 A>C), RS1001009390 (14:63318911 T>C,G), RS1001128486 (14:63315673 TC>T,TCC), RS1001396509 (14:63314866 T>C), RS1001764628 (14:63318592 G>A), RS1001855521 (14:63319575 T>G), RS1003017414 (14:63315050 A>G), RS1003237257 (14:63319587 T>C), RS1003437132 (14:63319912 C>T), RS1003616059 (14:63313809 C>G,T), RS1004266407 (14:63313622 T>C), RS1004416757 (14:63316928 C>A,T), RS1005139608 (14:63318091 T>G), RS1005536796 (14:63318259 G>T)

Disease associations

OMIM: gene MIM:609652 | 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
GCST010002_154	Refractive error	1.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	decreases methylation	1
Methylcholanthrene	affects binding, increases reaction	1
Valproic Acid	increases methylation	1
Sodium Selenite	increases expression	1

Clinical trials (associated diseases)

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