TLDC2

Summary

TLDC2 (TBC/LysM-associated domain containing 2, HGNC:16112) is a protein-coding gene on chromosome 20q11.23, encoding TLD domain-containing protein 2 (A0PJX2). Inhibits the activity of the vacuolar-type ATPase (V-ATPase) by inducing disassembly of the V-ATPase complex.

Predicted to be involved in response to oxidative stress. Predicted to act upstream of or within negative regulation of cellular response to oxidative stress. Predicted to be active in nucleus.

Source: NCBI Gene 140711 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 48 total
• MANE Select transcript: NM_080628

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16112
Approved symbol	TLDC2
Name	TBC/LysM-associated domain containing 2
Location	20q11.23
Locus type	gene with protein product
Status	Approved
Aliases	dJ132F21.2
Ensembl gene	ENSG00000101342
Ensembl biotype	protein_coding
Entrez	140711

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000217320, ENST00000436941, ENST00000602922, ENST00000866639, ENST00000866640, ENST00000866641, ENST00000866642, ENST00000866643, ENST00000866644, ENST00000866645, ENST00000866646

RefSeq mRNA: 2 — MANE Select: NM_080628 NM_001304783, NM_080628

CCDS: CCDS33465

Canonical transcript exons

ENST00000217320 — 7 exons

Exon	Start	End
ENSE00000661808	36880655	36880750
ENSE00000661809	36887455	36887528
ENSE00000800453	36879041	36879193
ENSE00000800454	36889251	36889403
ENSE00001377613	36876138	36876207
ENSE00001389618	36877899	36878054
ENSE00003559733	36892862	36894235

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 92.00.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5677 / max 136.9781, expressed in 66 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184455	0.3311	50
184457	0.2230	28
184456	0.0136	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	92.00	gold quality
mucosa of transverse colon	UBERON:0004991	91.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.90	gold quality
tibial nerve	UBERON:0001323	88.63	gold quality
monocyte	CL:0000576	84.03	gold quality
rectum	UBERON:0001052	83.95	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.86	gold quality
leukocyte	CL:0000738	83.38	gold quality
small intestine	UBERON:0002108	82.65	gold quality
transverse colon	UBERON:0001157	82.20	gold quality
granulocyte	CL:0000094	81.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.67	gold quality
right lung	UBERON:0002167	80.53	gold quality
mucosa of stomach	UBERON:0001199	80.20	gold quality
duodenum	UBERON:0002114	78.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	78.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	78.02	gold quality
lower esophagus	UBERON:0013473	77.92	gold quality
intestine	UBERON:0000160	77.49	gold quality
upper lobe of left lung	UBERON:0008952	77.42	gold quality
colonic epithelium	UBERON:0000397	77.13	gold quality
colon	UBERON:0001155	76.67	gold quality
large intestine	UBERON:0000059	76.13	gold quality
jejunal mucosa	UBERON:0000399	76.08	gold quality
upper lobe of lung	UBERON:0008948	75.15	gold quality
muscle layer of sigmoid colon	UBERON:0035805	75.09	gold quality
spleen	UBERON:0002106	74.49	gold quality
left coronary artery	UBERON:0001626	74.33	gold quality
right atrium auricular region	UBERON:0006631	74.15	gold quality
omental fat pad	UBERON:0010414	73.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	16.84
E-ANND-3	yes	3.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

62 targeting TLDC2, 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-4776-3P	100.00	68.73	1340
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-2392	99.43	67.50	708

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tldc2	ENSMUSG00000074628
rattus_norvegicus	Tldc2	ENSRNOG00000006395
drosophila_melanogaster	mtd	FBGN0013576
caenorhabditis_elegans		WBGENE00018700

Paralogs (3): NCOA7 (ENSG00000111912), MEAK7 (ENSG00000140950), OXR1 (ENSG00000164830)

Protein

Protein identifiers

TLD domain-containing protein 2 — A0PJX2 (reviewed: A0PJX2)

Alternative names: TBC/LysM-associated domain-containing protein 2

All UniProt accessions (2): A0PJX2, A2A2J3

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits the activity of the vacuolar-type ATPase (V-ATPase) by inducing disassembly of the V-ATPase complex. Protects neuronal cells against oxidative stress. Required for kidney bicarbonate secretion.

Subunit / interactions. Interacts (via TLDc domain) with vacuolar ATPase subunit ATP6V1B1.

Similarity. Belongs to the OXR1 family.

RefSeq proteins (2): NP_001291712, NP_542195* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006571	TLDc_dom	Domain

Pfam: PF07534

UniProt features (5 total): chain 1, domain 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0PJX2-F1	85.87	0.74

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 37 (showing top): chr20q11, MARTENS_TRETINOIN_RESPONSE_UP, STAMBOLSKY_TARGETS_OF_MUTATED_TP53_DN, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, CTR9_TARGET_GENES, DYRK1A_TARGET_GENES, E2F2_TARGET_GENES, HDAC4_TARGET_GENES, HES4_TARGET_GENES, HOXB6_TARGET_GENES, SIX1_TARGET_GENES, MIR548AJ_3P_MIR548X_3P, MIR548AE_3P_MIR548AQ_3P, MIR548AH_3P_MIR548AM_3P, MIR548J_3P

GO Biological Process (1): response to oxidative stress (GO:0006979)

GO Molecular Function (0):

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

230 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLDC2	CDC16	Q13042	608
TLDC2	SPEM2	Q0P670	602
TLDC2	LRRC24	Q50LG9	549
TLDC2	CIMAP2	Q3ZCV2	530
TLDC2	WDR17	Q8IZU2	501
TLDC2	APC2	O95996	464
TLDC2	USP6	P35125	446
TLDC2	SLC6A20	Q9NP91	386
TLDC2	SYT8	Q8NBV8	370
TLDC2	HTRA4	P83105	369
TLDC2	OR4C13	Q8NGP0	358
TLDC2	ZNF185	O15231	352
TLDC2	OR9K2	Q8NGE7	349
TLDC2	FREM3	P0C091	348
TLDC2	VARS1	P26640	347

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TLDC2	ATP6V1D	psi-mi:“MI:0914”(association)	0.530
TLDC2	ATP6V1B2	psi-mi:“MI:0914”(association)	0.350
MID1	TLDC2	psi-mi:“MI:0914”(association)	0.350
TLDC2	GLDC	psi-mi:“MI:0914”(association)	0.350
TLDC2	ATP6V1A	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): ATP6V1C1 (Affinity Capture-MS), ATP6V1D (Affinity Capture-MS), ATP6V1E1 (Affinity Capture-MS), ATP6V1B2 (Affinity Capture-MS), KLHL15 (Affinity Capture-MS), TLDC2 (Affinity Capture-RNA), ATP6V1C1 (Affinity Capture-MS), ATP6V1B2 (Affinity Capture-MS), TLDC2 (Affinity Capture-MS), ATP6V1E1 (Affinity Capture-MS), GLDC (Affinity Capture-MS), ATP6V1D (Affinity Capture-MS), ATP6V1G1 (Affinity Capture-MS), ATP6V1A (Affinity Capture-MS), ATP6V1F (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2MDK8, A0PJX2, A2ACG1, D3ZBP4, E2RDP2, F1MH07, O08644, O75038, O75064, O75636, P0C0K7, P0DPD7, P0DPE0, P0DPE1, P52824, Q00653, Q0IID2, Q1LWV7, Q3SYT1, Q3U1Y4, Q4KM32, Q4R380, Q5NCQ5, Q5RKI3, Q62137, Q684M2, Q68DD2, Q6ZSI9, Q86TL0, Q86XP0, Q8BGV9, Q8BX80, Q8C9V1, Q8NFF5, Q8NFI3, Q8R5G7, Q8TDZ2, Q8VDP3, Q8WWN8, Q91ZJ0

Diamond homologs: A0PJX2, A2ACG1, A5PKL1, A8KBE0, B4F6Q9, O14284, Q08952, Q0IID2, Q1LWV7, Q3UUG6, Q4KMM3, Q4V8B0, Q5ZJX5, Q5ZMS4, Q6C443, Q6CMK8, Q6DDZ9, Q6DFV7, Q6FSN5, Q6P9B6, Q755A3, Q874Z5, Q8K0P3, Q8N573, Q8NI08, Q9ULP9, Q9VIH7, Q5AEM5, P0CP42, P0CP43, Q6ZZF5, Q7S4P1, Q4I8S2, Q4WX99, Q5B8X6, A1A5K6, Q29RJ2, Q08CX5, Q6BJM5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	6
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1005 predictions. Top by Δscore:

Variant	Effect	Δscore
20:36877897:A:AG	acceptor_gain	1.0000
20:36877898:G:GG	acceptor_gain	1.0000
20:36887528:GGT:G	donor_loss	1.0000
20:36887529:GT:G	donor_loss	1.0000
20:36887530:T:A	donor_loss	1.0000
20:36889249:A:AG	acceptor_gain	1.0000
20:36889249:AGT:A	acceptor_gain	1.0000
20:36889250:G:GA	acceptor_gain	1.0000
20:36889250:GTG:G	acceptor_gain	1.0000
20:36876203:GGCTG:G	donor_gain	0.9900
20:36876204:GCTG:G	donor_gain	0.9900
20:36876204:GCTGG:G	donor_gain	0.9900
20:36876205:CTG:C	donor_loss	0.9900
20:36876206:TGGT:T	donor_loss	0.9900
20:36876207:GGTA:G	donor_loss	0.9900
20:36876208:G:A	donor_loss	0.9900
20:36876209:T:A	donor_loss	0.9900
20:36877895:GCA:G	acceptor_loss	0.9900
20:36877896:CA:C	acceptor_loss	0.9900
20:36877897:AG:A	acceptor_loss	0.9900
20:36877898:G:GT	acceptor_loss	0.9900
20:36877898:GC:G	acceptor_gain	0.9900
20:36877898:GCCC:G	acceptor_gain	0.9900
20:36877898:GCCCA:G	acceptor_gain	0.9900
20:36878003:GCCCC:G	donor_gain	0.9900
20:36878016:G:GT	donor_gain	0.9900
20:36878027:GGTTT:G	donor_gain	0.9900
20:36878096:C:G	donor_gain	0.9900
20:36879039:A:AG	acceptor_gain	0.9900
20:36879040:G:GG	acceptor_gain	0.9900

AlphaMissense

1403 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:36889315:T:C	F193L	0.994
20:36889317:C:A	F193L	0.994
20:36889317:C:G	F193L	0.994
20:36889348:T:C	F204L	0.989
20:36889350:C:A	F204L	0.989
20:36889350:C:G	F204L	0.989
20:36880727:T:C	F139L	0.987
20:36880729:C:A	F139L	0.987
20:36880729:C:G	F139L	0.987
20:36887458:T:C	F148L	0.986
20:36887460:T:A	F148L	0.986
20:36887460:T:G	F148L	0.986
20:36889297:A:C	S187R	0.986
20:36889299:C:A	S187R	0.986
20:36889299:C:G	S187R	0.986
20:36879092:T:C	F81L	0.985
20:36879094:C:A	F81L	0.985
20:36879094:C:G	F81L	0.985
20:36880700:T:C	F130L	0.985
20:36880702:C:A	F130L	0.985
20:36880702:C:G	F130L	0.985
20:36889262:G:A	G175E	0.981
20:36880662:G:A	G117E	0.980
20:36889315:T:A	F193I	0.979
20:36889316:T:C	F193S	0.979
20:36889308:C:G	C190W	0.978
20:36889323:C:A	N195K	0.977
20:36889323:C:G	N195K	0.977
20:36887494:G:A	G160R	0.974
20:36887494:G:C	G160R	0.974

dbSNP variants (sampled 300 via entrez): RS1000063381 (20:36891293 G>A), RS1000279103 (20:36888454 C>T), RS1000451420 (20:36880491 C>T), RS1000456348 (20:36883414 G>T), RS1000631100 (20:36888807 G>A), RS1000819080 (20:36876015 G>A,C), RS1000968361 (20:36878095 C>T), RS1001075408 (20:36883813 G>A), RS1001422082 (20:36877833 T>C), RS1001465910 (20:36887812 G>A), RS1001620208 (20:36879995 G>A), RS1001921179 (20:36892157 C>T), RS1002027866 (20:36875501 AC>A), RS1002076667 (20:36894405 G>A,T), RS1002188222 (20:36877592 G>A)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:612952, MIM:614415, MIM:225750

GenCC curated gene-disease

Mondo (3): Aicardi-Goutieres syndrome 5 (MONDO:0013059), chilblain lupus 2 (MONDO:0013739), Aicardi-Goutieres syndrome (MONDO:0018866)

Orphanet (1): Aicardi-Goutières syndrome (Orphanet:51)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002794_12	Airway wall thickness	8.000000e-06
GCST006087_25	Familial lung adenocarcinoma	4.000000e-06
GCST009391_1208	Metabolite levels	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006898	airway wall thickness measurement
EFO:0006953	family history of lung cancer
EFO:0010419	triacylglycerol 54:1 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535607	Aicardi-Goutieres syndrome (supp.)
C535608	Aicardi-Goutieres syndrome 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8124728	SAMHD1, TLDC2	3	2.75	1	stavudine

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1I3	Abcam A-549 TLDC2 KO 2	Cancer cell line	Male
CVCL_B2QL	Abcam A-549 TLDC2 KO 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02363452	PHASE2	COMPLETED	Reverse Transcriptase Inhibitors in AGS
NCT03921554	PHASE2	COMPLETED	JAK Inhibitor Treatment in AGS
NCT04731103	PHASE2	COMPLETED	Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome
NCT05613868	PHASE2	TERMINATED	TPN-101 in Aicardi-Goutières Syndrome (AGS)
NCT04517253	PHASE2/PHASE3	TERMINATED	A Study of Baricitinib (LY3009104) in Adult and Pediatric Japanese Participants With NNS/CANDLE, SAVI, and AGS
NCT03304717	PHASE1/PHASE2	WITHDRAWN	Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
NCT01724580	Not specified	APPROVED_FOR_MARKETING	Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT06898372	Not specified	COMPLETED	Evaluate the Efficacy of Anti-Jak1 Inhibitors as Treatment for Patients With Aicardi-Goutières Syndrome