TESPA1

Summary

TESPA1 (thymocyte expressed, positive selection associated 1, HGNC:29109) is a protein-coding gene on chromosome 12q13.2, encoding Protein TESPA1 (A2RU30). Required for the development and maturation of T-cells, its function being essential for the late stages of thymocyte development.

Predicted to enable phospholipase binding activity and signaling receptor binding activity. Predicted to be involved in COP9 signalosome assembly; positive regulation of T cell differentiation in thymus; and positive regulation of T cell receptor signaling pathway. Predicted to act upstream of or within TCR signalosome assembly. Located in cytosol. Part of COP9 signalosome.

Source: NCBI Gene 9840 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_001136030

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29109
Approved symbol	TESPA1
Name	thymocyte expressed, positive selection associated 1
Location	12q13.2
Locus type	gene with protein product
Status	Approved
Aliases	ITPRID3
Ensembl gene	ENSG00000135426
Ensembl biotype	protein_coding
OMIM	615664
Entrez	9840

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000316577, ENST00000449076, ENST00000524622, ENST00000524668, ENST00000524923, ENST00000524959, ENST00000525978, ENST00000526532, ENST00000528240, ENST00000531122, ENST00000532757, ENST00000532804, ENST00000533446, ENST00000533607, ENST00000868657, ENST00000868658, ENST00000868659, ENST00000868660

RefSeq mRNA: 12 — MANE Select: NM_001136030 NM_001098815, NM_001136030, NM_001261844, NM_001351148, NM_001351149, NM_001351150, NM_001351151, NM_001351152, NM_001351153, NM_001351154, NM_001351155, NM_014796

CCDS: CCDS44913, CCDS58240

Canonical transcript exons

ENST00000449076 — 11 exons

Exon	Start	End
ENSE00001607570	54948015	54950390
ENSE00001652605	54962431	54963242
ENSE00001663692	54984585	54984762
ENSE00002293878	54974400	54974607
ENSE00003459205	54967843	54967892
ENSE00003465316	54966053	54966151
ENSE00003465885	54963742	54963950
ENSE00003570170	54966388	54966424
ENSE00003572704	54961168	54961267
ENSE00003629039	54967183	54967236
ENSE00003637732	54973477	54973519

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 94.84.

FANTOM5 (CAGE): breadth broad, TPM avg 12.3416 / max 1582.3035, expressed in 357 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131392	7.3305	287
131379	3.3428	60
131391	0.3508	108
131394	0.2771	56
131393	0.2456	61
131380	0.1893	40
131384	0.1561	16
131382	0.1189	10
131390	0.1103	46
206734	0.0760	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	94.84	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.18	gold quality
right frontal lobe	UBERON:0002810	94.15	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.73	gold quality
anterior cingulate cortex	UBERON:0009835	93.15	gold quality
cingulate cortex	UBERON:0003027	93.10	gold quality
frontal cortex	UBERON:0001870	92.86	gold quality
granulocyte	CL:0000094	91.57	gold quality
neocortex	UBERON:0001950	91.29	gold quality
middle temporal gyrus	UBERON:0002771	90.21	gold quality
superior frontal gyrus	UBERON:0002661	89.37	gold quality
putamen	UBERON:0001874	88.74	gold quality
primary visual cortex	UBERON:0002436	88.56	gold quality
blood	UBERON:0000178	87.60	gold quality
postcentral gyrus	UBERON:0002581	87.20	gold quality
parietal lobe	UBERON:0001872	86.66	gold quality
occipital lobe	UBERON:0002021	85.91	gold quality
caudate nucleus	UBERON:0001873	85.77	gold quality
cerebral cortex	UBERON:0000956	85.22	gold quality
lymph node	UBERON:0000029	85.16	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.65	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.78	gold quality
orbitofrontal cortex	UBERON:0004167	81.68	gold quality
telencephalon	UBERON:0001893	81.37	gold quality
vermiform appendix	UBERON:0001154	81.14	gold quality
thymus	UBERON:0002370	79.65	gold quality
bone marrow cell	CL:0002092	78.90	gold quality
colonic epithelium	UBERON:0000397	78.02	gold quality
leukocyte	CL:0000738	77.14	gold quality
bone marrow	UBERON:0002371	76.87	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	622.02
E-CURD-112	yes	447.85
E-MTAB-9067	yes	431.95
E-HCAD-25	yes	396.01
E-MTAB-9388	yes	366.45
E-ANND-3	yes	11.94
E-MTAB-6701	yes	11.66
E-MTAB-9801	yes	8.60
E-GEOD-109979	no	152.53
E-MTAB-5061	no	3.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting TESPA1, 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-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-4496	99.88	68.89	2236
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-7978	99.86	66.90	856
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-1976	99.74	65.48	1127

Literature-anchored findings (GeneRIF, showing 7)

• Tespa1 is a novel component of mitochondria-associated endoplasmic reticulum membranes and affects mitochondrial calcium flux. (PMID:23501103)
• Tespa1 is post-translationally modified upon intracellular divalent calcium-ion Ca2+ increase in thymocytes. (PMID:23541577)
• The TESPA1 gene was found to not be involved in ankylosing spondylitis in a Chinese population. (PMID:24893580)
• Tespa1 hay have a role in susceptibility but not severity of rheumatoid arthritis in the Zhejiang Han population in China (PMID:25736038)
• Tespa1 functions in T cell development and the regulation of TCR-induced Ca(2+) signalling through IP3R1 (PMID:28598420)
• Thymic-specific regulation of TCR signaling by Tespa1. (PMID:31316154)
• Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging. (PMID:35705636)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	tespa1	ENSDARG00000053311
mus_musculus	Tespa1	ENSMUSG00000034833

Paralogs (2): ITPRID2 (ENSG00000138434), ITPRID1 (ENSG00000180347)

Protein

Protein identifiers

Protein TESPA1 — A2RU30 (reviewed: A2RU30)

Alternative names: Thymocyte-expressed positive selection-associated protein 1

All UniProt accessions (9): A2RU30, E9PHY9, E9PIN8, E9PIT9, E9PM24, E9PN46, E9PPW8, H0YDP3, H0YEX3

UniProt curated annotations — full annotation on UniProt →

Function. Required for the development and maturation of T-cells, its function being essential for the late stages of thymocyte development. Plays a role in T-cell antigen receptor (TCR)-mediated activation of the ERK and NFAT signaling pathways, possibly by serving as a scaffolding protein that promotes the assembly of the LAT signalosome in thymocytes. May play a role in the regulation of inositol 1,4,5-trisphosphate receptor-mediated Ca(2+) release and mitochondrial Ca(2+) uptake via the mitochondria-associated endoplasmic reticulum membrane (MAM) compartment.

Subunit / interactions. Interacts with PLCG1 and GRB2; the association is increased with prolonged stimulation of the TCR and may facilitate the assembly of the LAT signalosome. Interacts with ITPR1. Also interacts with ITPR3. Interacts with HSPA9.

Subcellular location. Cytoplasm. Endoplasmic reticulum membrane.

Post-translational modifications. May be phosphorylated in response to store-operated Ca(+2) entry.

Isoforms (3)

UniProt ID	Names	Canonical?
A2RU30-1	1	yes
A2RU30-2	2
A2RU30-3	3

RefSeq proteins (12): NP_001092285, NP_001129502, NP_001248773, NP_001338077, NP_001338078, NP_001338079, NP_001338080, NP_001338081, NP_001338082, NP_001338083, NP_001338084, NP_055611 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029325	ITPR-bd	Domain
IPR043444	TESPA1-like	Family

Pfam: PF14722

UniProt features (14 total): compositionally biased region 4, region of interest 2, mutagenesis site 2, splice variant 2, chain 1, sequence variant 1, sequence conflict 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A2RU30-F1	54.20	0.02

Functional residue map

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

Post-translational modifications (1): 311

Mutagenesis-validated functional residues (2):

Position	Phenotype
185	loss of itpr1-binding.
186	strong decrease in itpr1-binding. complete loss of itpr1-binding; when associated with a-185.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 155 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, MODULE_255, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, MODULE_317, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_REGULATION_OF_HEMOPOIESIS, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY

GO Biological Process (7): intracellular protein localization (GO:0008104), COP9 signalosome assembly (GO:0010387), T cell differentiation in thymus (GO:0033077), positive regulation of T cell differentiation in thymus (GO:0033089), TCR signalosome assembly (GO:0036399), positive regulation of T cell receptor signaling pathway (GO:0050862), regulation of T cell receptor signaling pathway (GO:0050856)

GO Molecular Function (2): signaling receptor binding (GO:0005102), phospholipase binding (GO:0043274)

GO Cellular Component (7): cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), COP9 signalosome (GO:0008180), TCR signalosome (GO:0036398), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein-containing complex assembly	2
T cell receptor signaling pathway	2
cytoplasm	2
macromolecule localization	1
T cell differentiation	1
T cell differentiation in thymus	1
regulation of T cell differentiation in thymus	1
positive regulation of T cell differentiation	1
regulation of T cell receptor signaling pathway	1
positive regulation of antigen receptor-mediated signaling pathway	1
regulation of antigen receptor-mediated signaling pathway	1
protein binding	1
enzyme binding	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
nuclear protein-containing complex	1
protein-containing complex	1
T cell receptor complex	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

658 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TESPA1	HSPA9	P30036	885
TESPA1	ITPR1	Q14643	833
TESPA1	ITPR3	Q14573	716
TESPA1	THEMIS	Q8N1K5	480
TESPA1	LAT	O43561	457
TESPA1	AIG1	Q9NVV5	450
TESPA1	RNF34	Q969K3	434
TESPA1	CD163L1	Q9NR16	429
TESPA1	RBM33	Q96EV2	424
TESPA1	TCF7	P36402	416
TESPA1	SUOX	P51687	406
TESPA1	TRMT13	Q9NUP7	396
TESPA1	PRSS22	Q9GZN4	394
TESPA1	CCL14	Q16627	387
TESPA1	RMDN3	Q96TC7	380

IntAct

5 interactions, top by confidence:

A	B	Type	Score
TESPA1	ITPRID2	psi-mi:“MI:0914”(association)	0.350
TESPA1	COL1A1	psi-mi:“MI:0914”(association)	0.350
TESPA1	PLCG1	psi-mi:“MI:0914”(association)	0.350
TESPA1		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): YWHAG (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), BOK (Affinity Capture-MS), ITPR2 (Affinity Capture-MS), ITPR3 (Affinity Capture-MS), ITPR1 (Affinity Capture-MS), SSFA2 (Affinity Capture-MS), KCMF1 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), ITPR1 (Affinity Capture-MS), ITPR3 (Affinity Capture-MS), ITPR2 (Affinity Capture-MS), BOK (Affinity Capture-MS), SSFA2 (Affinity Capture-MS), YWHAZ (Affinity Capture-MS)

ESM2 similar proteins: A2A7Y5, A2A9F4, A2ALU4, A2RU30, A2VE02, A6NGG8, A6NMK8, B1AXH1, B2RQL2, D2J0Y4, M3WHG5, Q08DN6, Q0VET5, Q14B48, Q2NL68, Q2YDE2, Q4V8B5, Q5DTX6, Q5JTC6, Q5JXC2, Q5RCQ2, Q5SX79, Q5XIK6, Q66JV7, Q6AY88, Q6AYH0, Q6GQV1, Q6NS69, Q6P1D7, Q6PAC4, Q6ZRS4, Q76N32, Q7TP36, Q7TSA6, Q7Z591, Q80VW7, Q811R2, Q86YN6, Q8BP99, Q8C0C4

Diamond homologs: A2RU30, P28290, Q14B48, Q3U132, Q6ZRS4, Q922B9, Q5REU9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1428 predictions. Top by Δscore:

Variant	Effect	Δscore
12:54963740:A:AC	donor_gain	1.0000
12:54963740:ACTGG:A	donor_gain	1.0000
12:54963741:C:CC	donor_gain	1.0000
12:54963741:CTGG:C	donor_gain	1.0000
12:54963741:CTGGC:C	donor_gain	1.0000
12:54963946:AGATG:A	acceptor_gain	1.0000
12:54963947:GATG:G	acceptor_gain	1.0000
12:54963948:ATG:A	acceptor_gain	1.0000
12:54963949:TG:T	acceptor_gain	1.0000
12:54963951:C:CC	acceptor_gain	1.0000
12:54963956:A:AC	acceptor_gain	1.0000
12:54966383:CTTA:C	donor_loss	1.0000
12:54966384:TTA:T	donor_loss	1.0000
12:54966385:TA:T	donor_loss	1.0000
12:54966386:ACCT:A	donor_loss	1.0000
12:54966387:C:CT	donor_loss	1.0000
12:54966425:C:CC	acceptor_gain	1.0000
12:54966431:A:T	acceptor_gain	1.0000
12:54950389:GC:G	acceptor_gain	0.9900
12:54950389:GCC:G	acceptor_loss	0.9900
12:54950390:CC:C	acceptor_gain	0.9900
12:54950390:CCT:C	acceptor_loss	0.9900
12:54950391:CTGCA:C	acceptor_loss	0.9900
12:54963178:A:C	acceptor_gain	0.9900
12:54963765:T:TA	donor_gain	0.9900
12:54963956:A:C	acceptor_gain	0.9900
12:54965388:C:CA	donor_gain	0.9900
12:54966149:CTC:C	acceptor_gain	0.9900
12:54966381:CACTT:C	donor_loss	0.9900
12:54966382:ACTT:A	donor_loss	0.9900

AlphaMissense

3469 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:54963206:G:T	A231D	0.999
12:54963207:C:G	A231P	0.999
12:54963235:A:C	F221L	0.998
12:54963235:A:T	F221L	0.998
12:54963236:A:G	F221S	0.998
12:54963237:A:G	F221L	0.998
12:54963798:A:G	F200S	0.998
12:54963887:A:C	F170L	0.998
12:54963887:A:T	F170L	0.998
12:54963888:A:G	F170S	0.998
12:54963889:A:G	F170L	0.998
12:54963183:A:G	S239P	0.997
12:54963216:C:G	A228P	0.997
12:54963239:C:A	R220M	0.997
12:54963795:A:G	L201P	0.997
12:54963842:A:C	F185L	0.997
12:54963842:A:T	F185L	0.997
12:54963843:A:G	F185S	0.997
12:54963844:A:G	F185L	0.997
12:54963173:G:A	S242F	0.996
12:54963174:A:G	S242P	0.996
12:54963182:G:A	S239F	0.996
12:54963186:A:C	Y238D	0.996
12:54963197:A:G	F234S	0.996
12:54963215:G:T	A228D	0.996
12:54963218:A:G	L227P	0.996
12:54963797:G:C	F200L	0.996
12:54963797:G:T	F200L	0.996
12:54963798:A:C	F200C	0.996
12:54963799:A:G	F200L	0.996

dbSNP variants (sampled 300 via entrez): RS1000017985 (12:54971411 C>A), RS1000044645 (12:54965087 CT>C), RS1000069885 (12:54983808 TG>T), RS1000239908 (12:54970781 A>C,G), RS1000240711 (12:54977292 A>G,T), RS1000253963 (12:54958925 A>C,G), RS1000273003 (12:54977525 A>G), RS1000286090 (12:54958434 C>T), RS1000294733 (12:54976913 G>A,C), RS1000326755 (12:54971159 A>G), RS1000457321 (12:54983228 A>T), RS1000591989 (12:54971053 T>G), RS1000608112 (12:54948177 G>A,T), RS1000622448 (12:54982151 C>G), RS1000850663 (12:54983519 C>G)

Disease associations

OMIM: gene MIM:615664 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002935_8	Lead levels	1.000000e-06
GCST007798_146	Asthma	2.000000e-09
GCST007800_27	Asthma (childhood onset)	8.000000e-13
GCST007995_38	Asthma (childhood onset)	1.000000e-10
GCST010042_62	Asthma	6.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, decreases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	increases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases abundance, decreases methylation	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	decreases expression, decreases reaction	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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