TSHB

Summary

TSHB (thyroid stimulating hormone subunit beta, HGNC:12372) is a protein-coding gene on chromosome 1p13.2, encoding Thyrotropin subunit beta (P01222). Indispensable for the control of thyroid structure and metabolism.

The four human glycoprotein hormones chorionic gonadotropin (CG), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) are dimers consisting of alpha and beta subunits that are associated noncovalently. The alpha subunits of these hormones are identical, however, their beta chains are unique and confer biological specificity. Thyroid stimulating hormone functions in the control of thyroid structure and metabolism. The protein encoded by this gene is the beta subunit of thyroid stimulating hormone. Mutations in this gene are associated with congenital central and secondary hypothyroidism and Hashimoto’s thyroiditis. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 7252 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated thyroid-stimulating hormone deficiency (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 84 total — 7 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 52
• MANE Select transcript: NM_000549

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12372
Approved symbol	TSHB
Name	thyroid stimulating hormone subunit beta
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134200
Ensembl biotype	protein_coding
OMIM	188540
Entrez	7252

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000256592

RefSeq mRNA: 1 — MANE Select: NM_000549 NM_000549

CCDS: CCDS880

Canonical transcript exons

ENST00000256592 — 3 exons

Exon	Start	End
ENSE00000913449	115033973	115034302
ENSE00000913450	115033362	115033524
ENSE00001372051	115029826	115029860

Expression profiles

Bgee: expression breadth ubiquitous, 150 present calls, max score 97.23.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5659 / max 1378.0729, expressed in 6 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4768	1.5659	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	97.23	gold quality
pituitary gland	UBERON:0000007	96.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.97	silver quality
buccal mucosa cell	CL:0002336	72.49	gold quality
tibialis anterior	UBERON:0001385	68.35	silver quality
tibial artery	UBERON:0007610	67.02	gold quality
popliteal artery	UBERON:0002250	67.00	gold quality
mucosa of stomach	UBERON:0001199	65.29	gold quality
pancreatic ductal cell	CL:0002079	63.77	silver quality
islet of Langerhans	UBERON:0000006	63.72	gold quality
aorta	UBERON:0000947	63.66	gold quality
descending thoracic aorta	UBERON:0002345	62.08	gold quality
body of uterus	UBERON:0009853	62.01	gold quality
calcaneal tendon	UBERON:0003701	60.24	gold quality
muscle layer of sigmoid colon	UBERON:0035805	60.00	gold quality
thoracic aorta	UBERON:0001515	59.53	gold quality
ascending aorta	UBERON:0001496	59.22	gold quality
secondary oocyte	CL:0000655	59.10	gold quality
lower esophagus muscularis layer	UBERON:0035833	58.93	gold quality
lower esophagus	UBERON:0013473	58.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	58.77	gold quality
smooth muscle tissue	UBERON:0001135	58.59	gold quality
upper leg skin	UBERON:0004262	57.80	gold quality
endometrium epithelium	UBERON:0004811	57.61	gold quality
left uterine tube	UBERON:0001303	57.57	gold quality
decidua	UBERON:0002450	56.55	gold quality
sigmoid colon	UBERON:0001159	56.37	gold quality
left coronary artery	UBERON:0001626	55.17	gold quality
deltoid	UBERON:0001476	55.01	silver quality
ileal mucosa	UBERON:0000331	53.63	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.29

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
SLC5A5	Activation

Upstream regulators (CollecTRI, top): CREBZF, ESR1, FOXC1, GATA2, HLF, LHX2, LHX3, LHX4, NCOR1, NFIB, NR1D1, NR4A1, PAX8, POU1F1, POU2F1, PROP1, RARA, RXRB, SIX1, SMAD4, STAT1, TEF, TFCP2, TGFB1, THRA, THRB, TTF1, ZFHX3

Literature-anchored findings (GeneRIF, showing 38)

• TSHbeta variants C105Vfs114X and Q49X are the most frequent cause of this severe disorder in Europe, now for the first time observed in compound heterozygous state. (PMID:15297803)
• Data suggest that the expression of Pit-1 in cells of the alpha SU-based gonadotropin cell lineage might also lead to the expression of growth hormone, prolactin, and thyroid-stimulating hormone beta subunit. (PMID:16133148)
• N-CoR and TRbeta cooperate in the regulation of the TSHbeta gene and this ligand-dependent repression is mediated by the LXXLL motif in N-CoR (PMID:16216492)
• Serum TSH is frequently suppressed after treatment with antithyroid drugs. (PMID:17954417)
• In a cohort of pregnant women without overt thyroid dysfunction, the risk of child loss increased with higher levels of maternal TSH. (PMID:19273570)
• Human pituitary, thyroid, and mononuclear leukocytes express a TSHbeta isoform that is analogous to the mouse TSHbeta isoform, consisting of a 27 nucleotide portion of intron 2 and all of exon 3, coding for 71.2% of the native human TSHbeta polypeptide. (PMID:19364510)
• Results suggest that a serum TSH concentration at the lower end of the reference range may be associated with low BMD in men. (PMID:20455884)
• Novel mutations of the TSH-beta subunit gene underlying congenital central hypothyroidism undetectable in neonatal TSH screening. (PMID:20534762)
• we describe two new sibships with isolated congenital central hypothyroidism due to two different homozygous TSHbeta gene mutations (c.Q49X and c.C105fs114X). (PMID:20553196)
• Studies indicate that immune system-derived TSH, in particular, a splice variant of TSHbeta that is preferentially made by cells of the immune system, is produced by a subset of hematopoietic cells that traffic to the thyroid. (PMID:20826543)
• T3 weakens TRb1 binding to a negative regulatory element in the TSHbeta promoter. (PMID:20838640)
• Data suggest that a progressive increase in TSH are predictive factors for thyroid failure in Hashimoto’s thyroiditis (HT) patients. (PMID:21981142)
• Data suggest that likelihood of papillary thyroid carcinoma is reduced when serum TSH is lower, as in thyroid autonomy, and increased when serum TSH is higher, as in thyroid autoimmunity. [Meta-Analysis; REVIEW] (PMID:22278420)
• In Hashimoto’s thyroiditis the hTSHbeta splice variant exists in human serum and dimerises with TSHalpha. (PMID:22752807)
• The use of these age-specific reference intervals for TSH, especially in those over 70 years old, would result in the reclassification of many TSH results from “abnormal” to “normal” and avoid unnecessary treatment. (PMID:23345094)
• bTSH Induces IL-6 Protein and mRNA in Orbital Fibroblasts and Fibrocytes (PMID:24086448)
• Epistasis between single nucleotide polymorphisms within the TSHB and ADAMTS16 genes may increase the risk of premature ovarian failure in Korean women. (PMID:24366283)
• High Thyroid Stimulating Hormone levels are associated with papillary thyroid carcinoma. (PMID:24595799)
• In cases with isolated central congenital hypothyroidism and undetectably low TSH serum concentrations, a TSHbeta gene deletion should be considered (PMID:25012771)
• Serum TSH was associated with pulse wave velocity on population level when adjusted with age and sex. (PMID:25185682)
• Higher TSH levels are associated with less favorable lipid levels in children (PMID:25781359)
• analysis of a single nucleotide substitution in TSHbeta related to clinical euthyroidism [family case report] (PMID:25950606)
• Findings defined the immune-derived functional TSHb splice variant that resided in the thyroid of patients with Hashimoto’s thyroiditis (HT), which exerted the unique effects on the pathogenesis of the disease. (PMID:26170068)
• Data suggest that the subtle thyroid-stimulating hormone (TSH) reduction could possibly reflect minor hypothalamic-pituitary damage. (PMID:26432979)
• The serum levels of IL-8, MIP-1 alpha, MIP-1 beta, MMP-8, Resistin, FLRG, and BCAM were significantly higher in breast cancer patients, but LAP and TSH-beta levels were lower. (PMID:26898119)
• In hyperthyroidism, bone marrow resident macrophages have the potential to exert enhanced osteoprotective effects by oversecreting a TSH-beta splice variant. (PMID:27300765)
• the distribution of 1(st) trimester TSH and evaluate its association with perinatal outcomes and future development of maternal thyrotoxicosis, is reported. (PMID:27351808)
• In the context of metabolic syndrome, a higher TSH within the euthyroid range confers an increased leptin/adiponectin ratio, a proposed marker of atherosclerosis susceptibility and adipocyte dysfunction. (PMID:28077136)
• Serum macro TSH level is associated with sleep quality in patients with cardiovascular risks. (PMID:28287185)
• present the cases of two siblings with a novel mutation of TSHB. One of them was c.40A>G (rs10776792) which is a very common variation that is also seen in healthy individuals, the other was c.94G>A at codon 32 of exon 2 which resulted in a change from glutamic acid to lysine (p.E32K (PMID:28515030)
• results provide novel evidence of TSHB as a paracrine factor that is modulated in parallel with cholesterol metabolism in human adipose tissue (PMID:28646016)
• TSH level was found to be independently correlated with both carotid plaque prevalence and intima-media thickness. (PMID:30940720)
• Report of TSHB mutation causing central congenital hypothyroidism in a Brazilian family. (PMID:31166470)
• The Pathogenic TSH beta-subunit Variant C105Vfs114X Causes a Modified Signaling Profile at TSHR. (PMID:31703413)
• dentification of a mutation in the TSHbeta gene reinforces the importance of identifying ICCH that can occur in the absence of elevated serum TSH and demonstrates the functional significance of the TSHbeta cysteine knot. (PMID:31914441)
• Cold Exposure Distinctively Modulates Parathyroid and Thyroid Hormones in Cold-Acclimatized and Non-Acclimatized Humans. (PMID:32242612)
• The Human TSHbeta Subunit Proteins and Their Binding Sites on the TSH Receptor Using Molecular Dynamics Simulation. (PMID:32738139)
• GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. (PMID:32769997)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tshba	ENSDARG00000033726
danio_rerio		ENSDARG00000110110
mus_musculus	Tshb	ENSMUSG00000027857
rattus_norvegicus	Tshb	ENSRNOG00000016793
drosophila_melanogaster	Gpb5	FBGN0063368

Paralogs (9): CGB2 (ENSG00000104818), LHB (ENSG00000104826), CGB3 (ENSG00000104827), FSHB (ENSG00000131808), GPHB5 (ENSG00000179600), CGB5 (ENSG00000189052), CGB7 (ENSG00000196337), CGB8 (ENSG00000213030), CGB1 (ENSG00000267631)

Protein

Protein identifiers

Thyrotropin subunit beta — P01222 (reviewed: P01222)

Alternative names: Thyroid-stimulating hormone subunit beta, Thyrotropin beta chain

All UniProt accessions (1): P01222

UniProt curated annotations — full annotation on UniProt →

Function. Indispensable for the control of thyroid structure and metabolism.

Subunit / interactions. Heterodimer of a common alpha chain and a unique beta chain which confers biological specificity to thyrotropin, lutropin, follitropin and gonadotropin.

Subcellular location. Secreted.

Disease relevance. Hypothyroidism, congenital, non-goitrous, 4 (CHNG4) [MIM:275100] A form of central hypothyroidism, a disorder characterized by insufficient stimulation by thyroid stimulating hormone of an otherwise normal thyroid gland. CHNG4 is an autosomal recessive form characterized by isolated thyrotropin deficiency that, if untreated, results in severe growth retardation and intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Major isoform in peripheral blood leukocytes and thyroid, may form heterodimers with isoform 1.

Similarity. Belongs to the glycoprotein hormones subunit beta family.

Isoforms (2)

UniProt ID	Names	Canonical?
P01222-1	1	yes
P01222-2	2

RefSeq proteins (1): NP_000540* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001545	Gonadotropin_bsu	Family
IPR006208	Glyco_hormone_CN	Domain
IPR018245	Gonadotropin_bsu_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00007

UniProt features (23 total): disulfide bond 6, strand 5, sequence variant 3, turn 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1, helix 1, propeptide 1, glycosylation site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7UTZ	ELECTRON MICROSCOPY	2.4
7T9I	ELECTRON MICROSCOPY	2.9
7XW5	ELECTRON MICROSCOPY	2.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01222-F1	86.28	0.58

Antibody-complex structures (SAbDab): 3 — 7T9I, 7UTZ, 7XW5

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 (6): 22–72, 36–87, 39–125, 47–103, 51–105, 108–115

Glycosylation sites (1): 43

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-209822	Glycoprotein hormones
R-HSA-209968	Thyroxine biosynthesis
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 247 (showing top): MODULE_92, TSENG_IRS1_TARGETS_UP, MORF_RAD51L3, GOBP_CELL_CELL_SIGNALING, EVI1_05, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, MODULE_289, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, MORF_CTSB, REACTOME_HORMONE_LIGAND_BINDING_RECEPTORS, KEGG_AUTOIMMUNE_THYROID_DISEASE, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, HP1SITEFACTOR_Q6, TGACATY_UNKNOWN

GO Biological Process (4): G protein-coupled receptor signaling pathway (GO:0007186), cell-cell signaling (GO:0007267), anatomical structure morphogenesis (GO:0009653), signal transduction (GO:0007165)

GO Molecular Function (2): hormone activity (GO:0005179), signaling receptor binding (GO:0005102)

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

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Peptide hormone biosynthesis	1
Metabolism of amine-derived hormones	1
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
cellular anatomical structure	2
G protein-coupled receptor activity	1
signal transduction	1
developmental process	1
anatomical structure development	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
protein binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSHB	CGA	P01215	981
TSHB	TRH	P20396	920
TSHB	TRHR	P34981	894
TSHB	POU1F1	P28069	893
TSHB	TSHR	P16473	886
TSHB	PRL	P01236	861
TSHB	POMC	P01189	788
TSHB	DIO2	Q92813	787
TSHB	GPHA2	Q96T91	768
TSHB	FSHR	P23945	766
TSHB	TEF	Q10587	752
TSHB	LHX3	Q9UBR4	700
TSHB	EYA3	Q99504	692
TSHB	DBP	Q10586	680
TSHB	PAX8	Q06710	668

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TSHB	GPHA2	psi-mi:“MI:0915”(physical association)	0.370
TSHB	SMCHD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): ERC1 (Affinity Capture-MS), SMCHD1 (Affinity Capture-MS), EPDR1 (Affinity Capture-MS), ASB1 (Affinity Capture-MS), RICTOR (Affinity Capture-MS), TINAG (Affinity Capture-MS), CNTNAP3 (Affinity Capture-MS), SP3 (Affinity Capture-MS), PRMT3 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), HLA-C (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), ANKRD46 (Affinity Capture-MS)

ESM2 similar proteins: A0A0F7YZI5, A0A0F7Z3J2, B0VXV3, B0VXV4, C0K3N1, C0K3N2, C0K3N3, O13050, O73824, P01222, P01223, P01224, P04652, P0DW98, P10257, P12656, P30971, P37240, P48250, P48252, P49764, P52584, P52585, P54828, P67861, P67863, P79357, Q08127, Q28376, Q330K6, Q52R90, Q566B2, Q566B3, Q6J936, Q6SI68, Q7ZZV4, Q90X23, Q90X24, Q91120, Q925Q4

Diamond homologs: A1BN60, A1BN61, A6NKQ9, O09108, O13050, O46430, 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, P10257, P12656, P12837, P18427, P19794, P25330

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
TGFB1	“down-regulates quantity by repression”	TSHB	“transcriptional regulation”
TSHB	“up-regulates quantity by stabilization”	SLC5A5
TSHB	“up-regulates quantity by expression”	SLC5A5	“transcriptional regulation”
TSHB	“form complex”	TSH	binding
POU1F1	“up-regulates quantity by expression”	TSHB	“transcriptional regulation”
GATA2	“up-regulates quantity by expression”	TSHB	“transcriptional regulation”
TSHB	up-regulates	TSHR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	3
Uncertain significance	30
Likely benign	34
Benign	5

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
12685	NM_000549.5(TSHB):c.94G>T (p.Glu32Ter)	Pathogenic
12688	NM_000549.5(TSHB):c.162+5G>A	Pathogenic
2761301	NM_000549.5(TSHB):c.28del (p.Leu10fs)	Pathogenic
2840951	NM_000549.5(TSHB):c.250del (p.Ile84fs)	Pathogenic
3247895	NC_000001.10:g.(?115575984)(115576848_?)del	Pathogenic
3691392	NM_000549.5(TSHB):c.226_227del (p.Asp76fs)	Pathogenic
437070	NM_000549.5(TSHB):c.373del (p.Cys125fs)	Pathogenic
1048762	NM_000549.5(TSHB):c.108_109del (p.Ala37fs)	Likely pathogenic
3574752	NM_000549.5(TSHB):c.-1_5del (p.Met1_Thr2del)	Likely pathogenic
3574990	NM_000549.5(TSHB):c.315T>A (p.Cys105Ter)	Likely pathogenic

SpliceAI

321 predictions. Top by Δscore:

Variant	Effect	Δscore
1:115033404:ATGT:A	acceptor_gain	0.9900
1:115033404:ATGTG:A	acceptor_gain	0.9900
1:115033405:T:G	acceptor_gain	0.9900
1:115033967:CCCCA:C	acceptor_loss	0.9900
1:115033968:CCCAG:C	acceptor_loss	0.9900
1:115033969:CCAGG:C	acceptor_loss	0.9900
1:115033970:CA:C	acceptor_loss	0.9900
1:115033971:A:AG	acceptor_gain	0.9900
1:115033971:AG:A	acceptor_gain	0.9900
1:115033972:G:A	acceptor_loss	0.9900
1:115033972:G:GG	acceptor_gain	0.9900
1:115033972:GG:G	acceptor_gain	0.9900
1:115033972:GGAT:G	acceptor_gain	0.9900
1:115029856:GTAAG:G	donor_gain	0.9800
1:115030795:G:GT	donor_gain	0.9800
1:115033379:T:A	acceptor_gain	0.9800
1:115029857:TAAGG:T	donor_loss	0.9700
1:115029860:GGTA:G	donor_loss	0.9700
1:115029862:T:G	donor_loss	0.9700
1:115033959:T:TA	acceptor_loss	0.9700
1:115032257:ACCT:A	donor_gain	0.9600
1:115033360:A:AG	acceptor_gain	0.9600
1:115033361:G:GG	acceptor_gain	0.9600
1:115033404:A:AG	acceptor_gain	0.9600
1:115030835:C:G	donor_gain	0.9500
1:115033361:GC:G	acceptor_gain	0.9500
1:115033361:GCAT:G	acceptor_gain	0.9500
1:115033404:AT:A	acceptor_gain	0.9100
1:115033395:T:TA	acceptor_gain	0.8900
1:115033408:G:A	acceptor_gain	0.8700

AlphaMissense

908 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:115033501:T:A	C47S	0.995
1:115033502:G:C	C47S	0.995
1:115034024:T:A	C72S	0.995
1:115034025:G:C	C72S	0.995
1:115033501:T:C	C47R	0.994
1:115033502:G:A	C47Y	0.994
1:115033503:T:G	C47W	0.994
1:115034024:T:C	C72R	0.994
1:115033515:T:G	C51W	0.993
1:115034026:C:G	C72W	0.993
1:115034132:T:A	C108S	0.993
1:115034133:G:C	C108S	0.993
1:115033514:G:A	C51Y	0.992
1:115034025:G:A	C72Y	0.992
1:115033513:T:A	C51S	0.991
1:115033514:G:C	C51S	0.991
1:115034117:T:A	C103S	0.991
1:115034118:G:C	C103S	0.991
1:115034099:T:G	Y97D	0.990
1:115034118:G:A	C103Y	0.990
1:115033502:G:T	C47F	0.989
1:115033513:T:C	C51R	0.989
1:115034069:T:A	C87S	0.989
1:115034069:T:C	C87R	0.989
1:115034070:G:C	C87S	0.989
1:115034109:C:A	A100D	0.989
1:115034025:G:T	C72F	0.988
1:115034132:T:C	C108R	0.988
1:115034153:T:A	C115S	0.988
1:115034154:G:C	C115S	0.988

dbSNP variants (sampled 300 via entrez): RS1000119238 (1:115034561 A>T), RS1000341892 (1:115028159 C>G,T), RS1000583799 (1:115033818 G>A), RS1002089286 (1:115029314 T>C), RS1002223087 (1:115032322 G>C), RS1002647241 (1:115032010 T>G), RS1002719186 (1:115031642 A>G), RS1002751648 (1:115031100 T>A), RS1002828163 (1:115032601 TA>T,TAA), RS1002940970 (1:115030858 G>C), RS1003693306 (1:115030929 G>T), RS1005771179 (1:115031965 A>G), RS1005844138 (1:115032298 GA>G,GAA), RS1006095271 (1:115031564 G>A), RS1006919901 (1:115028536 T>A,C)

Disease associations

OMIM: gene MIM:188540 | disease phenotypes: MIM:275100

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated thyroid-stimulating hormone deficiency	Definitive	Autosomal recessive

Mondo (1): isolated thyroid-stimulating hormone deficiency (MONDO:0010139)

Orphanet (1): Isolated thyroid-stimulating hormone deficiency (Orphanet:90674)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000053	Macroorchidism
HP:0000158	Macroglossia
HP:0000260	Wide anterior fontanel
HP:0000270	Delayed cranial suture closure
HP:0000282	Facial edema
HP:0000716	Depression
HP:0000821	Hypothyroidism
HP:0000853	Goiter
HP:0000870	Increased circulating prolactin concentration
HP:0000958	Dry skin
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001537	Umbilical hernia
HP:0001539	Omphalocele
HP:0001609	Hoarse voice
HP:0001615	Hoarse cry
HP:0001662	Bradycardia
HP:0002019	Constipation
HP:0002045	Hypothermia
HP:0002312	Clumsiness
HP:0002690	Large sella turcica
HP:0002750	Delayed skeletal maturation
HP:0003124	Hypercholesterolemia
HP:0003265	Neonatal hyperbilirubinemia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009305_2	California verbal learning test score	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
perfluorooctane sulfonic acid	decreases expression, decreases secretion, increases secretion	3
Cyclic AMP	decreases reaction, increases abundance, increases activity, affects binding	3
perfluorooctanoic acid	decreases secretion, increases secretion	2
Octreotide	decreases secretion, affects activity, decreases reaction	2
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases reaction, increases abundance, increases activity	1
alfacalcidol	increases reaction, increases expression	1
3-phenoxybenzoic acid	increases abundance, increases expression	1
beta-hexachlorocyclohexane	affects expression, affects secretion	1
diisobutyl phthalate	decreases secretion, increases abundance	1
2,2’,3’,4,4’,5-hexachlorobiphenyl	affects secretion, affects expression	1
sodium perchlorate	increases reaction, affects abundance, decreases reaction	1
thiocyanate	increases expression	1
9-deoxy-delta-9-prostaglandin D2	increases expression, increases reaction	1
2,3,3’,4,4’-pentachlorobiphenyl	affects expression, affects secretion	1
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid	increases abundance, increases expression	1
2,3’,4,4’,5-pentachlorobiphenyl	affects expression, affects secretion	1
mono(2-ethyl-5-oxohexyl)phthalate	decreases secretion, increases abundance	1
pentabromodiphenyl ether	decreases reaction, increases secretion	1
15-deoxy-delta(12,14)-prostaglandin J2	increases expression, increases reaction	1
efavirenz	affects cotreatment, increases expression, affects abundance, increases reaction, decreases reaction	1
perfluoro-n-nonanoic acid	decreases secretion	1
N-(2-hydroxybenzyl)glycine	affects binding, decreases reaction, increases abundance	1
PCB 180	affects expression, affects secretion	1
dipyrido(3,2-a-2’,3’-c)phenazine	affects binding, decreases reaction, increases abundance	1
perchlorate	affects cotreatment, increases expression	1
2,2’,4,4’,5-pentachlorobiphenyl	affects expression, affects secretion	1
Org 41841	affects binding, decreases reaction, increases activity, increases expression	1
2,4,4’,5-tetrachlorobiphenyl	affects expression, affects secretion	1
bisphenol S	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns