TREH

Summary

TREH (trehalase, HGNC:12266) is a protein-coding gene on chromosome 11q23.3, encoding Trehalase (O43280). Intestinal trehalase is probably involved in the hydrolysis of ingested trehalose.

This gene encodes an enzyme that hydrolyses trehalose, a disaccharide formed from two glucose molecules found mainly in fungi, plants, and insects. A partial duplication of this gene is located adjacent to this locus on chromosome 11. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 11181 — RefSeq curated summary.

At a glance

• Gene–disease (curated): diarrhea-vomiting due to trehalase deficiency (Supportive, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 102 total
• Phenotypes (HPO): 7
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_007180

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12266
Approved symbol	TREH
Name	trehalase
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	TRE, TREA, MGC129621
Ensembl gene	ENSG00000118094
Ensembl biotype	protein_coding
OMIM	275360
Entrez	11181

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000264029, ENST00000397925, ENST00000527558, ENST00000531295, ENST00000613915, ENST00000854539

RefSeq mRNA: 2 — MANE Select: NM_007180 NM_001301065, NM_007180

CCDS: CCDS73401, CCDS73402

Canonical transcript exons

ENST00000264029 — 15 exons

Exon	Start	End
ENSE00000796071	118658680	118658733
ENSE00000796072	118658905	118659017
ENSE00000796073	118659370	118659481
ENSE00000796074	118659747	118659964
ENSE00000796076	118660866	118660915
ENSE00000796077	118661160	118661282
ENSE00001302378	118657316	118658441
ENSE00003461195	118662881	118662968
ENSE00003494992	118661890	118661990
ENSE00003512150	118663339	118663439
ENSE00003583528	118661637	118661729
ENSE00003585564	118663052	118663196
ENSE00003652439	118660539	118660733
ENSE00003652500	118661393	118661509
ENSE00003721071	118679539	118679650

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 93.26.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1609 / max 90.0600, expressed in 22 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122613	0.1327	19
122614	0.0282	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	93.26	gold quality
duodenum	UBERON:0002114	92.11	gold quality
small intestine	UBERON:0002108	81.94	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.27	gold quality
adult mammalian kidney	UBERON:0000082	75.44	gold quality
ileal mucosa	UBERON:0000331	74.66	silver quality
gall bladder	UBERON:0002110	73.13	gold quality
right lobe of liver	UBERON:0001114	72.10	gold quality
sural nerve	UBERON:0015488	71.77	gold quality
stromal cell of endometrium	CL:0002255	71.42	gold quality
mucosa of transverse colon	UBERON:0004991	69.94	gold quality
jejunum	UBERON:0002115	69.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.95	gold quality
kidney	UBERON:0002113	68.51	gold quality
pancreatic ductal cell	CL:0002079	67.19	silver quality
rectum	UBERON:0001052	67.14	gold quality
lower esophagus mucosa	UBERON:0035834	66.11	gold quality
metanephros cortex	UBERON:0010533	65.78	gold quality
body of stomach	UBERON:0001161	65.76	gold quality
transverse colon	UBERON:0001157	65.73	gold quality
cortex of kidney	UBERON:0001225	65.59	gold quality
body of pancreas	UBERON:0001150	64.16	gold quality
liver	UBERON:0002107	63.95	gold quality
intestine	UBERON:0000160	63.92	gold quality
esophagus mucosa	UBERON:0002469	63.70	gold quality
right atrium auricular region	UBERON:0006631	63.36	gold quality
left uterine tube	UBERON:0001303	62.97	gold quality
stomach	UBERON:0000945	62.49	gold quality
cardiac atrium	UBERON:0002081	62.20	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.36
E-MTAB-6075	no	96.82

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 6)

• These results suggest that TREH acts as a stress-response protein in the kidney rather than involved in utilization of exogenous trehalose. (PMID:19126402)
• we found three protective alleles for glioma patients, including the allele ‘‘T’’ of rs17748 in the TREH gene by recessive model (OR, 0.48; 95% CI, 0.23-1.01; P = 0.05) analysis (PMID:22369735)
• variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. (PMID:23468175)
• results suggest a significant association between the RETL1, TREH, and PHLDB1 genes and GBM development in the Han Chinese population (PMID:26156397)
• In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human Osteoarthritis, which may serve as a new target for future therapies. (PMID:27701424)
• these results indicate that trehalose has anti-apoptotic effects through the suppression of oxidative stress-induced mitochondrial injury and ER stress which is dependent on the promotion of autophagic flux and the induction of selective autophagy (PMID:28981117)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	treh	ENSDARG00000077911
mus_musculus	Treh	ENSMUSG00000032098
rattus_norvegicus	Treh	ENSRNOG00000052010
drosophila_melanogaster	Treh	FBGN0003748
drosophila_melanogaster	CG6262	FBGN0034121
caenorhabditis_elegans	tre-1	WBGENE00006607
caenorhabditis_elegans		WBGENE00006608
caenorhabditis_elegans		WBGENE00006609
caenorhabditis_elegans		WBGENE00006610
caenorhabditis_elegans		WBGENE00006611

Protein

Protein identifiers

Trehalase — O43280 (reviewed: O43280)

Alternative names: Alpha,alpha-trehalase, Alpha,alpha-trehalose glucohydrolase

All UniProt accessions (2): O43280, A0A087WTJ4

UniProt curated annotations — full annotation on UniProt →

Function. Intestinal trehalase is probably involved in the hydrolysis of ingested trehalose.

Subunit / interactions. Homodimer; disulfide-linked.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in kidney, liver and small intestine. Also more weakly expressed in pancreas.

Disease relevance. Trehalase deficiency (TREHD) [MIM:612119] An autosomal recessive condition characterized by the inability to digest trehalose, a disaccharide found in mushrooms, products containing baker’s yeast, and dried food. Individuals with trehalase deficiency suffer from abdominal pain, increased rectal flatulence, and diarrhea due to osmotic water flow into the colon. The gene represented in this entry is involved in disease pathogenesis.

Similarity. Belongs to the glycosyl hydrolase 37 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43280-1	1	yes
O43280-2	2

RefSeq proteins (2): NP_001287994, NP_009111* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001661	Glyco_hydro_37	Family
IPR008928	6-hairpin_glycosidase_sf	Homologous_superfamily
IPR012341	6hp_glycosidase-like_sf	Homologous_superfamily
IPR018232	Glyco_hydro_37_CS	Conserved_site

Pfam: PF01204

Enzyme classification (BRENDA):

• EC 3.2.1.28 — alpha,alpha-trehalase (BRENDA: 90 organisms, 95 substrates, 318 inhibitors, 114 Km, 29 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ALPHA,ALPHA-TREHALOSE	0.06–72.8	59
TREHALOSE	0.0109–55	50

Catalyzed reactions (Rhea), 1 shown:

• alpha,alpha-trehalose + H2O = alpha-D-glucose + beta-D-glucose (RHEA:32675)

UniProt features (24 total): binding site 7, sequence variant 5, glycosylation site 4, active site 2, signal peptide 1, chain 1, lipid moiety-binding region 1, splice variant 1, propeptide 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43280-F1	92.80	0.90

Functional residue map

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

Catalytic / active sites (2): 321 (proton donor/acceptor); 514 (proton donor/acceptor)

Ligand- & substrate-binding residues (7): 319; 529; 168; 175–176; 212; 221–223; 286–288

Post-translational modifications (1): 556

Glycosylation sites (4): 78, 239, 261, 369

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-189085	Digestion of dietary carbohydrate

MSigDB gene sets: 71 (showing top): GOBP_OLIGOSACCHARIDE_METABOLIC_PROCESS, REACTOME_DIGESTION_OF_DIETARY_CARBOHYDRATE, GOBP_OLIGOSACCHARIDE_CATABOLIC_PROCESS, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, HNF4_DR1_Q3, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, KEGG_STARCH_AND_SUCROSE_METABOLISM, GOBP_CARBOHYDRATE_CATABOLIC_PROCESS, GOCC_SIDE_OF_MEMBRANE, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_GLYCOSYL_BONDS, YOSHIMURA_MAPK8_TARGETS_UP, MULLIGHAN_MLL_SIGNATURE_1_DN, HNF4ALPHA_Q6, GOMF_HYDROLASE_ACTIVITY_HYDROLYZING_O_GLYCOSYL_COMPOUNDS, CHEN_METABOLIC_SYNDROM_NETWORK

GO Biological Process (4): trehalose metabolic process (GO:0005991), trehalose catabolic process (GO:0005993), animal organ morphogenesis (GO:0009887), carbohydrate metabolic process (GO:0005975)

GO Molecular Function (3): alpha,alpha-trehalase activity (GO:0004555), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (4): plasma membrane (GO:0005886), membrane (GO:0016020), extracellular exosome (GO:0070062), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Digestion	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane	2
cellular anatomical structure	2
disaccharide metabolic process	1
trehalose metabolic process	1
disaccharide catabolic process	1
anatomical structure morphogenesis	1
animal organ development	1
primary metabolic process	1
trehalase activity	1
catalytic activity	1
hydrolase activity	1
cell periphery	1
extracellular vesicle	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

1885 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TREH	MGAM	O43451	779
TREH	SI	P14410	737
TREH	MGAM2	Q2M2H8	734
TREH	PABPN1	Q86U42	712
TREH	PGM3	O95394	592
TREH	AMY2A	P04746	591
TREH	UGP2	Q16851	591
TREH	PYGL	P06737	582
TREH	PYGB	P11216	582
TREH	PYGM	P11217	577
TREH	PGGHG	Q32M88	575
TREH	GPI	P06744	574
TREH	AMY1B	P04745	565
TREH	PHLDB1	Q86UU1	563
TREH	NTHL1	P78549	560

IntAct

2 interactions, top by confidence:

A	B	Type	Score
TREH	GPAA1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (2): GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMP0, A4IG42, A5PJN5, A6QLU7, A6QQ07, F1N2K1, O00462, O18835, O43280, O77695, O95479, O97524, P08236, P10253, P12265, P19813, P70699, P82450, Q3U4H6, Q4FAT7, Q4FZV0, Q5E985, Q5FVF9, Q5R5N6, Q5R7A9, Q5R8R3, Q5RFU0, Q5XHI4, Q641Z7, Q6P6V7, Q6P7A9, Q6QR59, Q6RHW4, Q76HN1, Q865R1, Q8BFW6, Q8BNE1, Q8BP56, Q8C0L6, Q8CFX1

Diamond homologs: A1AAC5, A1AH61, A7ZKW9, A7ZT60, A7ZZD1, A8A5X9, A8AFT6, A8J4S9, A9MLK7, A9MVX4, B0RNH1, B1IU96, B1J0B4, B1LHA4, B1LJ63, B1X7X4, B1XAN8, B2U4I7, B4SUI9, B4SWF1, B4T8D8, B4TXW7, B4TZ02, B5BI56, B5F4F0, B5F9H0, B5FKM4, B5FTN7, B5R2X4, B5R404, B5R904, B5RGS3, B5YVG5, B6I385, B6I9Q8, B7L603, B7LGV7, B7LSZ0, B7LXB1, B7M3D0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CDK1	“up-regulates activity”	TREH	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	19
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2780 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118658734:C:CC	acceptor_gain	1.0000
11:118659833:C:CA	donor_gain	1.0000
11:118661207:T:A	donor_gain	1.0000
11:118661208:C:A	donor_gain	1.0000
11:118661391:A:AC	donor_gain	1.0000
11:118661392:C:CC	donor_gain	1.0000
11:118663046:TCATA:T	donor_loss	1.0000
11:118663047:CATAC:C	donor_loss	1.0000
11:118663048:ATAC:A	donor_loss	1.0000
11:118663049:TACCT:T	donor_loss	1.0000
11:118663050:A:AT	donor_loss	1.0000
11:118663051:C:CT	donor_loss	1.0000
11:118663051:CCTGT:C	donor_gain	1.0000
11:118663059:T:A	donor_gain	1.0000
11:118663440:C:CC	acceptor_gain	1.0000
11:118658730:CATA:C	acceptor_gain	0.9900
11:118658732:TA:T	acceptor_gain	0.9900
11:118659365:CCTA:C	donor_loss	0.9900
11:118659366:CTACC:C	donor_loss	0.9900
11:118659367:TA:T	donor_loss	0.9900
11:118659368:A:G	donor_loss	0.9900
11:118659369:CCT:C	donor_gain	0.9900
11:118659748:T:TA	donor_gain	0.9900
11:118660541:AG:A	donor_gain	0.9900
11:118660665:A:T	acceptor_gain	0.9900
11:118660667:C:CT	acceptor_gain	0.9900
11:118660860:GCTCA:G	donor_loss	0.9900
11:118660861:CTCAC:C	donor_loss	0.9900
11:118660862:TCA:T	donor_loss	0.9900
11:118660863:CACCT:C	donor_loss	0.9900

AlphaMissense

3785 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118658433:A:C	F536L	0.998
11:118658433:A:T	F536L	0.998
11:118658435:A:G	F536L	0.998
11:118661907:A:C	F169L	0.998
11:118661907:A:T	F169L	0.998
11:118661909:A:G	F169L	0.998
11:118661160:C:A	R286M	0.997
11:118661160:C:G	R286T	0.997
11:118658429:A:G	W538R	0.995
11:118658429:A:T	W538R	0.995
11:118660896:C:G	D293H	0.995
11:118660915:C:A	R286S	0.995
11:118660915:C:G	R286S	0.995
11:118661483:C:G	R215P	0.995
11:118659415:C:G	D463H	0.994
11:118659418:A:G	W462R	0.994
11:118659418:A:T	W462R	0.994
11:118660675:G:C	F322L	0.994
11:118660675:G:T	F322L	0.994
11:118660677:A:G	F322L	0.994
11:118660678:G:C	D321E	0.994
11:118660678:G:T	D321E	0.994
11:118660679:T:A	D321V	0.994
11:118662901:A:G	W135R	0.994
11:118662901:A:T	W135R	0.994
11:118663373:C:A	K52N	0.994
11:118663373:C:G	K52N	0.994
11:118659416:C:A	W462C	0.993
11:118659416:C:G	W462C	0.993
11:118660680:C:G	D321H	0.993

dbSNP variants (sampled 300 via entrez): RS1000269510 (11:118657612 T>C), RS1000600962 (11:118677182 G>A,C), RS1000654618 (11:118669204 G>A), RS1000714997 (11:118676799 C>A,T), RS1000943185 (11:118669725 C>G,T), RS1000975533 (11:118664099 A>C,G), RS1001429600 (11:118665807 A>C), RS1001501944 (11:118677277 C>T), RS1001859552 (11:118664538 C>T), RS1001931708 (11:118670560 T>G), RS1002059662 (11:118677684 C>G), RS1002435417 (11:118664759 G>C,T), RS1002745273 (11:118681420 G>A), RS1003136556 (11:118673592 G>A,T), RS1003190403 (11:118679711 C>T)

Disease associations

OMIM: gene MIM:275360 | disease phenotypes: MIM:612119

GenCC curated gene-disease

Disease	Classification	Inheritance
diarrhea-vomiting due to trehalase deficiency	Supportive	Autosomal dominant

Mondo (1): diarrhea-vomiting due to trehalase deficiency (MONDO:0012803)

Orphanet (1): Trehalase deficiency (Orphanet:103909)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002027	Abdominal pain
HP:0003270	Abdominal distention
HP:0012379	Abnormal circulating enzyme concentration or activity

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000817_136	Height	2.000000e-08
GCST001670_2	Vitiligo	2.000000e-09
GCST002388_19	Serum metabolite levels	3.000000e-30
GCST003853_6	Hip minimal joint space width	2.000000e-07
GCST005523_30	Celiac disease	2.000000e-11
GCST005531_22	Multiple sclerosis	8.000000e-11
GCST005534_4	Systemic sclerosis	1.000000e-07
GCST005535_1	Diffuse cutaneous systemic sclerosis	3.000000e-06
GCST005990_14	Non-albumin protein levels	2.000000e-08
GCST006612_66	LDL cholesterol	8.000000e-11
GCST008489_5	Celiac disease	2.000000e-08
GCST009652_17	Serum alkaline phosphatase levels	1.000000e-09
GCST010002_199	Refractive error	3.000000e-34
GCST90011900_61	Serum alkaline phosphatase levels	7.000000e-39

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007873	cartilage thickness measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562603	Trehalase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3087 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,739 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL307429	DUVOGLUSTAT	2	4,739

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.75	Ki	180	nM	SALBOSTATIN

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
aristolochic acid I	increases expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Acetaminophen	decreases expression	1
Arbutin	decreases expression	1
Hydrocortisone	decreases activity	1
Aflatoxin B1	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL812720	Binding	Evaluated for the inhibition of trehalase from porcine kidneys	Total synthesis of trehalase inhibitor salbostatin — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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