THNSL2

Summary

THNSL2 (threonine synthase like 2, HGNC:25602) is a protein-coding gene on chromosome 2p11.2, encoding Threonine synthase-like 2 (Q86YJ6). Acts as a catabolic phospho-lyase on both gamma- and beta-phosphorylated substrates.

This gene encodes a threonine synthase-like protein. A similar enzyme in mouse can catalyze the degradation of O-phospho-homoserine to a-ketobutyrate, phosphate, and ammonia. This protein also has phospho-lyase activity on both gamma and beta phosphorylated substrates. In mouse an alternatively spliced form of this protein has been shown to act as a cytokine and can induce the production of the inflammatory cytokine IL6 in osteoblasts. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 55258 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 94 total
• MANE Select transcript: NM_018271

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25602
Approved symbol	THNSL2
Name	threonine synthase like 2
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10916, TSH2, SOFAT
Ensembl gene	ENSG00000144115
Ensembl biotype	protein_coding
OMIM	611261
Entrez	55258

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 12 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000324166, ENST00000343544, ENST00000377254, ENST00000419759, ENST00000449349, ENST00000464022, ENST00000475910, ENST00000476349, ENST00000496165, ENST00000496844, ENST00000674169, ENST00000674282, ENST00000674334, ENST00000906990, ENST00000906991, ENST00000906992, ENST00000947207, ENST00000947208

RefSeq mRNA: 5 — MANE Select: NM_018271 NM_001244676, NM_001244678, NM_001384382, NM_001384383, NM_018271

CCDS: CCDS2002, CCDS58718, CCDS74539, CCDS92801

Canonical transcript exons

ENST00000674334 — 9 exons

Exon	Start	End
ENSE00001076288	88185328	88185479
ENSE00001285360	88173139	88173373
ENSE00003503744	88182699	88182847
ENSE00003533451	88178783	88179013
ENSE00003579125	88174639	88174833
ENSE00003621957	88182948	88183073
ENSE00003743973	88175249	88175401
ENSE00003898180	88170346	88170456
ENSE00003898369	88185898	88186627

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 93.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6472 / max 69.8018, expressed in 1112 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21344	5.6472	1112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	93.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.88	gold quality
gastrocnemius	UBERON:0001388	93.73	gold quality
muscle of leg	UBERON:0001383	92.74	gold quality
adenohypophysis	UBERON:0002196	92.73	gold quality
right adrenal gland cortex	UBERON:0035827	92.67	gold quality
pituitary gland	UBERON:0000007	92.01	gold quality
right adrenal gland	UBERON:0001233	91.91	gold quality
apex of heart	UBERON:0002098	91.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.75	gold quality
left lobe of thyroid gland	UBERON:0001120	90.44	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.15	gold quality
right lobe of thyroid gland	UBERON:0001119	90.13	gold quality
triceps brachii	UBERON:0001509	90.08	silver quality
right uterine tube	UBERON:0001302	90.00	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.72	gold quality
lower esophagus	UBERON:0013473	89.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.64	gold quality
mucosa of stomach	UBERON:0001199	89.56	gold quality
mucosa of transverse colon	UBERON:0004991	89.52	gold quality
muscle organ	UBERON:0001630	89.27	gold quality
thyroid gland	UBERON:0002046	89.26	gold quality
tibial nerve	UBERON:0001323	88.20	gold quality
adult mammalian kidney	UBERON:0000082	88.19	gold quality
right atrium auricular region	UBERON:0006631	88.10	gold quality
right ovary	UBERON:0002118	87.96	gold quality
left adrenal gland	UBERON:0001234	87.89	gold quality
liver	UBERON:0002107	87.24	gold quality
gluteal muscle	UBERON:0002000	87.17	silver quality
adrenal cortex	UBERON:0001235	86.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting THNSL2, 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-6825-5P	99.96	69.81	3431
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-6884-3P	98.05	65.32	750
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-6854-5P	96.77	65.96	848
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969
HSA-MIR-6761-3P	77.17	65.96	50

Literature-anchored findings (GeneRIF, showing 8)

• A cytokine named SOFAT (secreted osteoclastogenic factor of activated T cells) can induce osteoblastic IL-6 production and osteoclast formation in the absence of osteoblasts or RANKL. It is insensitive to RANKL inhibitor osteoprotegerin. (PMID:19877052)
• THNSL2 was found to have bimodal expression in human skeletal muscle tissue. (PMID:21299892)
• The present study demonstrated that SOFAT may play an important role in periodontitis. (PMID:23619471)
• may exacerbate inflammation and support osteoclast formation and bone destruction (PMID:25916677)
• Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women. (PMID:26480920)
• These data support a putative role of SOFAT in the bone loss associated with chronic periodontal disease. (PMID:27035849)
• this study shows that SOFAT is a putative marker of osteoclasts in bone lesions (PMID:29489507)
• Secreted Osteoclastogenic Factor of Activated T Cells (SOFAT) Is Associated With Rheumatoid Arthritis and Joint Pain: Initial Evidences of a New Pathway. (PMID:32849501)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	thnsl2	ENSDARG00000032584
mus_musculus	Thnsl2	ENSMUSG00000054474
rattus_norvegicus	Thnsl2	ENSRNOG00000006508
caenorhabditis_elegans		WBGENE00007653
caenorhabditis_elegans		WBGENE00008490
caenorhabditis_elegans		WBGENE00008732
caenorhabditis_elegans		WBGENE00010759
caenorhabditis_elegans		WBGENE00019094
caenorhabditis_elegans		WBGENE00019096
caenorhabditis_elegans		WBGENE00019962

Paralogs (5): SDS (ENSG00000135094), SDSL (ENSG00000139410), CBS (ENSG00000160200), SRR (ENSG00000167720), THNSL1 (ENSG00000185875)

Protein

Protein identifiers

Threonine synthase-like 2 — Q86YJ6 (reviewed: Q86YJ6)

Alternative names: Secreted osteoclastogenic factor of activated T-cells

All UniProt accessions (4): Q86YJ6, A8K0C1, C9J3J1, C9JU10

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a catabolic phospho-lyase on both gamma- and beta-phosphorylated substrates. Degrades O-phospho-threonine (PThr) to alpha-ketobutyrate, ammonia and phosphate. Potent inducer of osteoblastic production of IL6. May act to exacerbate inflammation and/or bone turnover under inflammatory conditions.

Subcellular location. Secreted.

Similarity. Belongs to the threonine synthase family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q86YJ6-1	1	yes
Q86YJ6-2	2
Q86YJ6-3	3
Q86YJ6-4	4
Q86YJ6-5	SOFAT

RefSeq proteins (5): NP_001231605, NP_001231607, NP_001371311, NP_001371312, NP_060741* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001926	TrpB-like_PALP	Domain
IPR004450	Thr_synthase-like	Family
IPR029144	Thr_synth_N	Domain
IPR036052	TrpB-like_PALP_sf	Homologous_superfamily
IPR037158	Thr_synth_N_sf	Homologous_superfamily
IPR051166	Threonine_Synthase	Family

Pfam: PF00291, PF14821

UniProt features (12 total): splice variant 5, sequence variant 4, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86YJ6-F1	95.48	0.92

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): 113

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 80 (showing top): GOMF_CYTOKINE_ACTIVITY, chr2p11, GOMF_SIGNALING_RECEPTOR_BINDING, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, PARENT_MTOR_SIGNALING_UP, GOMF_AMINO_ACID_BINDING, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_PHOSPHORIC_ESTER_HYDROLASE_ACTIVITY, GOMF_ORGANIC_ACID_BINDING, GOMF_VITAMIN_BINDING, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, CHYLA_CBFA2T3_TARGETS_UP, DELACROIX_RAR_BOUND_ES, LIM_MAMMARY_STEM_CELL_DN, GOMF_PHOSPHATASE_ACTIVITY

GO Biological Process (3): obsolete serine family amino acid catabolic process (GO:0009071), 2-oxobutyrate biosynthetic process (GO:0046360), signal transduction (GO:0007165)

GO Molecular Function (5): cytokine activity (GO:0005125), phosphatase activity (GO:0016791), lyase activity (GO:0016829), pyridoxal phosphate binding (GO:0030170), serine binding (GO:0070905)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
short-chain fatty acid biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
phosphoric ester hydrolase activity	1
catalytic activity	1
anion binding	1
vitamin B6 binding	1
amino acid binding	1
carboxylic acid binding	1
cation binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1288 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THNSL2	SPMIP9	Q96LM6	568
THNSL2	CCDC172	P0C7W6	489
THNSL2	FOXI3	A8MTJ6	479
THNSL2	LYPLAL1	Q5VWZ2	478
THNSL2	SMYD1	Q8NB12	476
THNSL2	A0A0J9YXS1	A0A0J9YXS1	454
THNSL2	TNFSF11	O14788	445
THNSL2	CCDC200	A0A1B0GVQ3	444
THNSL2	UBOX5	O94941	430
THNSL2	ZNF366	Q8N895	428
THNSL2	KRCC1	Q9NPI7	419
THNSL2	PRSS45P	Q7RTY3	400
THNSL2	LZTS3	O60299	396
THNSL2	ZNF367	Q7RTV3	389
THNSL2	CTH	P32929	384

IntAct

4 interactions, top by confidence:

A	B	Type	Score
THNSL2	PCNA	psi-mi:“MI:0915”(physical association)	0.370
THNSL2	ZBTB16	psi-mi:“MI:0915”(physical association)	0.000
ARPC3	THNSL2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): ZBTB16 (Two-hybrid), THNSL2 (Co-fractionation)

ESM2 similar proteins: A0JPE9, A2AJL3, A2VD33, O46504, O75191, P12276, P12785, P13439, P17256, P19096, P31754, Q08D86, Q0IH28, Q0VFE7, Q3MIF4, Q3SYZ6, Q3TNA1, Q4V831, Q4V9P6, Q503J2, Q566S6, Q5M7T9, Q5R979, Q5RFE6, Q5U5V2, Q5XH07, Q5XIG6, Q5ZMJ4, Q64FG0, Q68FH4, Q6DCD1, Q6DH69, Q6GMR7, Q6GP95, Q6NUM9, Q6NUW9, Q6ZS86, Q71SP7, Q7TSQ8, Q80SY6

Diamond homologs: J9VI85, O24924, P00934, P16120, P23669, P27735, P29363, P37145, P44503, P57289, Q00063, Q2YDP8, Q42598, Q5M7T9, Q5R5P3, Q5RFE6, Q5XH07, Q80W22, Q86YJ6, Q89AR5, Q8BH55, Q8IYQ7, Q8K9V1, Q9BH05, Q9ZMX5, P45837, P66903, P9WG58, P9WG59, P09123

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1622 predictions. Top by Δscore:

Variant	Effect	Δscore
2:88178777:T:TA	acceptor_gain	1.0000
2:88178778:G:A	acceptor_gain	1.0000
2:88178780:CAGTG:C	acceptor_loss	1.0000
2:88178781:A:AG	acceptor_gain	1.0000
2:88178781:AGT:A	acceptor_gain	1.0000
2:88178781:AGTG:A	acceptor_gain	1.0000
2:88178782:G:A	acceptor_loss	1.0000
2:88178782:G:GA	acceptor_gain	1.0000
2:88178782:GT:G	acceptor_gain	1.0000
2:88178782:GTG:G	acceptor_gain	1.0000
2:88178782:GTGG:G	acceptor_gain	1.0000
2:88178782:GTGGA:G	acceptor_gain	1.0000
2:88182690:T:A	acceptor_gain	1.0000
2:88182697:A:G	acceptor_gain	1.0000
2:88183071:AAG:A	donor_loss	1.0000
2:88183073:GGT:G	donor_loss	1.0000
2:88183074:G:GC	donor_loss	1.0000
2:88185327:GC:G	acceptor_gain	1.0000
2:88173371:ATGGT:A	donor_loss	0.9900
2:88173372:TGG:T	donor_loss	0.9900
2:88173373:GGT:G	donor_loss	0.9900
2:88173374:GT:G	donor_loss	0.9900
2:88173375:TGAG:T	donor_loss	0.9900
2:88173376:GAGT:G	donor_loss	0.9900
2:88174808:G:GT	donor_gain	0.9900
2:88174827:GTT:G	donor_gain	0.9900
2:88174830:G:GG	donor_gain	0.9900
2:88179009:TGCAG:T	donor_loss	0.9900
2:88179010:GCAGG:G	donor_loss	0.9900
2:88179011:CAG:C	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000041503 (2:88179591 G>A), RS1000062188 (2:88173512 T>C,G), RS1000075820 (2:88179815 A>G), RS1000502816 (2:88173712 A>C,G), RS1000732315 (2:88182122 A>C), RS1000812607 (2:88186970 G>A), RS1000978030 (2:88175502 A>G,T), RS1001049068 (2:88180926 G>T), RS1001177064 (2:88177151 G>T), RS1001202441 (2:88180123 A>G,T), RS1001460576 (2:88183577 C>T), RS1001594596 (2:88179957 A>C), RS1001628760 (2:88180176 G>A), RS1001988868 (2:88182186 A>G), RS1002101282 (2:88186639 G>A)

Disease associations

OMIM: gene MIM:611261 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001525_36	Visceral fat	2.000000e-08
GCST003133_8	Plasma clusterin levels	5.000000e-06
GCST005896_19	Non-melanoma skin cancer	8.000000e-10
GCST006988_205	Blond vs. brown/black hair color	6.000000e-15
GCST90011900_4	Serum alkaline phosphatase levels	3.000000e-17
GCST90013410_36	Basal cell carcinoma	5.000000e-21

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007656	plasma clusterin measurement
EFO:0009260	non-melanoma skin carcinoma
EFO:0003924	hair color
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Aflatoxin B1	affects expression, decreases methylation	2
aristolochic acid I	increases expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
cinnamaldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
nickel sulfate	decreases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Carbamazepine	affects expression	1
Cyclophosphamide	affects cotreatment, affects response to substance	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	affects response to substance, affects cotreatment	1
Estradiol	decreases expression	1
Fluorouracil	affects cotreatment, affects response to substance	1
Methapyrilene	increases methylation	1
Smoke	decreases expression	1
Valproic Acid	affects expression	1
Cyclosporine	decreases expression	1
Paclitaxel	affects cotreatment, affects response to substance	1
Gold Compounds	increases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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