TMTC1

Summary

TMTC1 (transmembrane O-mannosyltransferase targeting cadherins 1, HGNC:24099) is a protein-coding gene on chromosome 12p11.22, encoding Protein O-mannosyl-transferase TMTC1 (Q8IUR5). Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.

Enables dolichyl-phosphate-mannose-protein mannosyltransferase activity. Involved in protein O-linked mannosylation. Predicted to be located in endoplasmic reticulum and membrane.

Source: NCBI Gene 83857 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 165 total
• MANE Select transcript: NM_001193451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24099
Approved symbol	TMTC1
Name	transmembrane O-mannosyltransferase targeting cadherins 1
Location	12p11.22
Locus type	gene with protein product
Status	Approved
Aliases	ARG99, OLF, FLJ31400, FLJ41625
Ensembl gene	ENSG00000133687
Ensembl biotype	protein_coding
OMIM	615855
Entrez	83857

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 19 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000256062, ENST00000319685, ENST00000539277, ENST00000546582, ENST00000550354, ENST00000551659, ENST00000552618, ENST00000552925, ENST00000553189, ENST00000904146, ENST00000904147, ENST00000904150, ENST00000939868, ENST00000939869, ENST00000939870, ENST00000944474, ENST00000944475, ENST00000944476, ENST00000944477, ENST00000944478, ENST00000944479, ENST00000944480, ENST00000944481

RefSeq mRNA: 3 — MANE Select: NM_001193451 NM_001193451, NM_001367875, NM_175861

CCDS: CCDS53772, CCDS8718, CCDS91670

Canonical transcript exons

ENST00000539277 — 18 exons

Exon	Start	End
ENSE00002218183	29500840	29506986
ENSE00002262364	29783450	29783942
ENSE00003494342	29518472	29518607
ENSE00003502743	29751666	29751872
ENSE00003504808	29517427	29517571
ENSE00003515857	29556857	29557000
ENSE00003554020	29520618	29520720
ENSE00003574592	29767898	29768075
ENSE00003584629	29512043	29512120
ENSE00003590181	29516349	29516486
ENSE00003598534	29755709	29755885
ENSE00003607297	29572105	29572218
ENSE00003609592	29536209	29536317
ENSE00003630476	29604178	29604299
ENSE00003644532	29583407	29583574
ENSE00003659992	29758704	29758777
ENSE00003676331	29514482	29514604
ENSE00003692517	29633147	29633336

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 98.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.9748 / max 69.6343, expressed in 1038 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130314	3.8968	1033
130310	0.0780	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
dorsal root ganglion	UBERON:0000044	98.06	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.45	gold quality
trigeminal ganglion	UBERON:0001675	97.38	gold quality
endothelial cell	CL:0000115	96.22	gold quality
lateral globus pallidus	UBERON:0002476	96.19	gold quality
pericardium	UBERON:0002407	95.63	gold quality
left ventricle myocardium	UBERON:0006566	95.60	gold quality
deltoid	UBERON:0001476	95.59	gold quality
mammary duct	UBERON:0001765	95.58	gold quality
epithelium of mammary gland	UBERON:0003244	95.44	gold quality
layer of synovial tissue	UBERON:0007616	94.99	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.79	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.52	gold quality
synovial joint	UBERON:0002217	94.27	gold quality
tibialis anterior	UBERON:0001385	94.12	gold quality
decidua	UBERON:0002450	94.11	gold quality
superficial temporal artery	UBERON:0001614	93.81	gold quality
substantia nigra pars compacta	UBERON:0001965	93.64	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.06	gold quality
entorhinal cortex	UBERON:0002728	92.89	gold quality
kidney epithelium	UBERON:0004819	92.70	gold quality
middle temporal gyrus	UBERON:0002771	92.65	gold quality
myocardium	UBERON:0002349	92.60	gold quality
quadriceps femoris	UBERON:0001377	92.47	gold quality
popliteal artery	UBERON:0002250	92.30	gold quality
tibial artery	UBERON:0007610	92.28	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.16	gold quality
thoracic mammary gland	UBERON:0005200	92.08	gold quality
mammary gland	UBERON:0001911	92.04	gold quality
parietal pleura	UBERON:0002400	92.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	33.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• findings provide an important link between aneuploidy and the stress pathways activated by Aurora B inhibition and also support the use of Aurora B inhibitors in combination therapy for treatment of cancer. (PMID:24764305)
• O-mannosylation pathway dedicated to cadherins/ protocadherins orchestrated by the four TMTC1-4 genes (PMID:28973932)
• Conserved sequence motifs in human TMTC1, TMTC2, TMTC3, and TMTC4, new O-mannosyltransferases from the GT-C/PMT clan, are rationalized as ligand binding sites. (PMID:33436046)
• TMTC1 promotes invasiveness of ovarian cancer cells through integrins beta1 and beta4. (PMID:37221403)
• Hypomethylation and high expression of the TMTC1 gene in patients with schizophrenia. (PMID:38232443)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmtc1	ENSDARG00000063149
mus_musculus	Tmtc1	ENSMUSG00000030306
rattus_norvegicus	Tmtc1	ENSRNOG00000001854

Paralogs (14): IFT88 (ENSG00000032742), TTC7A (ENSG00000068724), TMTC4 (ENSG00000125247), TMTC3 (ENSG00000139324), TTC6 (ENSG00000139865), BBS4 (ENSG00000140463), TTC13 (ENSG00000143643), OGT (ENSG00000147162), CFAP70 (ENSG00000156042), TTC8 (ENSG00000165533), TTC7B (ENSG00000165914), TTC16 (ENSG00000167094), TMTC2 (ENSG00000179104), TTC34 (ENSG00000215912)

Protein

Protein identifiers

Protein O-mannosyl-transferase TMTC1 — Q8IUR5 (reviewed: Q8IUR5)

Alternative names: Transmembrane O-mannosyltransferase targeting cadherins 1, Transmembrane and tetratricopeptide repeat-containing 1

All UniProt accessions (4): Q8IUR5, F8VTQ9, F8VXU8, H0YIB9

UniProt curated annotations — full annotation on UniProt →

Function. Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. The 4 members of the TMTC family are O-mannosyl-transferases dedicated primarily to the cadherin superfamily, each member seems to have a distinct role in decorating the cadherin domains with O-linked mannose glycans at specific regions. Also acts as O-mannosyl-transferase on other proteins such as PDIA3.

Subunit / interactions. May interact with FAM168B.

Subcellular location. Membrane. Endoplasmic reticulum.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the TMTC family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8IUR5-5	5	yes
Q8IUR5-1	1
Q8IUR5-2	2
Q8IUR5-3	3
Q8IUR5-4	4

RefSeq proteins (3): NP_001180380, NP_001354804, NP_787057 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003107	HAT	Repeat
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR013105	TPR_2	Repeat
IPR013618	TMTC_DUF1736	Domain
IPR019734	TPR_rpt	Repeat
IPR052943	TMTC_O-mannosyl-trnsfr	Family

Pfam: PF07719, PF08409, PF13424, PF13432, PF14559

Catalyzed reactions (Rhea), 2 shown:

• a di-trans,poly-cis-dolichyl beta-D-mannosyl phosphate + L-seryl-[protein] = 3-O-(alpha-D-mannosyl)-L-seryl-[protein] + a di-trans,poly-cis-dolichyl phosphate + H(+) (RHEA:17377)
• a di-trans,poly-cis-dolichyl beta-D-mannosyl phosphate + L-threonyl-[protein] = 3-O-(alpha-D-mannosyl)-L-threonyl-[protein] + a di-trans,poly-cis-dolichyl phosphate + H(+) (RHEA:53396)

UniProt features (46 total): topological domain 12, transmembrane region 11, repeat 10, splice variant 8, region of interest 2, compositionally biased region 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUR5-F1	88.13	0.79

Functional residue map

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

Glycosylation sites (1): 86

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 162 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, TGCGCANK_UNKNOWN, CCAWYNNGAAR_UNKNOWN, GOZGIT_ESR1_TARGETS_DN, TGACCTY_ERR1_Q2, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, chr12p11, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, HIF1_Q3, HOOI_ST7_TARGETS_DN, CUI_TCF21_TARGETS_2_DN, LINDVALL_IMMORTALIZED_BY_TERT_UP, PIT1_Q6, GOBP_PROTEIN_O_LINKED_GLYCOSYLATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN

GO Biological Process (3): RNA processing (GO:0006396), protein O-linked glycosylation via mannose (GO:0035269), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (4): mannosyltransferase activity (GO:0000030), dolichyl-phosphate-mannose-protein mannosyltransferase activity (GO:0004169), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (2): endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
protein O-linked glycosylation	1
hexosyltransferase activity	1
mannosyltransferase activity	1
protein O-linked glycosylation via mannose	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMTC1	DRD1	P21728	920
TMTC1	GNAL	P38405	871
TMTC1	EBF1	Q9UH73	843
TMTC1	EBF2	Q9HAK2	839
TMTC1	EBF4	Q9BQW3	808
TMTC1	OMP	P47874	793
TMTC1	RIC8B	Q9NVN3	784
TMTC1	GRHPR	Q9UBQ7	768
TMTC1	ADORA2A	P29274	728
TMTC1	ADCY3	O60266	711
TMTC1	RGS2	P41220	673
TMTC1	RIC8A	Q9NPQ8	671
TMTC1	EBF3	Q9H4W6	661
TMTC1	ADCY2	Q08462	657
TMTC1	SIRT3	Q9NTG7	642

IntAct

2 interactions, top by confidence:

A	B	Type	Score
Fam168b	TMTC1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (9): TMTC1 (Two-hybrid), TMTC1 (Affinity Capture-MS), TMTC1 (Affinity Capture-MS), TMTC1 (Affinity Capture-RNA), TMTC1 (Synthetic Lethality), JPH2 (Proximity Label-MS), TMTC1 (Proximity Label-MS), TMTC1 (Affinity Capture-RNA), TMTC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2M425, A1L1J9, B0BNG2, O60725, O75908, O77759, O88269, O88908, O95255, Q0P4J9, Q290J8, Q3T1L5, Q3TAE8, Q3UV71, Q499P8, Q49LS7, Q4R4E1, Q4VV71, Q5F380, Q5KR61, Q5R8F6, Q5RAH7, Q5RKL5, Q6AZ83, Q6NVG1, Q7SXZ1, Q7T310, Q7TPN3, Q7TQM4, Q86VD9, Q8AVI9, Q8BTP0, Q8C0T0, Q8C3X8, Q8CI59, Q8IUR5, Q8K2A8, Q8L638, Q8R1J1, Q8R4P9

Diamond homologs: P54389, Q8IUR5, Q20144, Q3UV71, Q56A06, Q5T4D3, Q6DCD5, Q6ZXV5, Q7K4B6, Q8BG19, Q8BRH0, Q8N394, Q9VF81, Q9VQE9, Q9V3X5, Q6CT48, Q6FM42

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	129
Likely benign	10
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

4279 predictions. Top by Δscore:

Variant	Effect	Δscore
12:29506621:T:TA	donor_gain	1.0000
12:29506622:C:A	donor_gain	1.0000
12:29506817:AT:A	donor_gain	1.0000
12:29512037:TCCTA:T	donor_loss	1.0000
12:29512038:CCTA:C	donor_loss	1.0000
12:29512039:CTAC:C	donor_loss	1.0000
12:29512040:TA:T	donor_loss	1.0000
12:29512041:A:C	donor_loss	1.0000
12:29512042:CC:C	donor_loss	1.0000
12:29512119:CT:C	acceptor_gain	1.0000
12:29512121:C:CC	acceptor_gain	1.0000
12:29514476:TTATA:T	donor_loss	1.0000
12:29514477:TATA:T	donor_loss	1.0000
12:29514479:TACCT:T	donor_loss	1.0000
12:29514480:ACC:A	donor_loss	1.0000
12:29514481:C:CT	donor_loss	1.0000
12:29514614:T:C	acceptor_gain	1.0000
12:29514614:T:TC	acceptor_gain	1.0000
12:29516344:TTTAC:T	donor_loss	1.0000
12:29516345:TTA:T	donor_loss	1.0000
12:29516346:TA:T	donor_loss	1.0000
12:29516347:A:AG	donor_loss	1.0000
12:29516348:C:A	donor_loss	1.0000
12:29518471:CCG:C	donor_gain	1.0000
12:29518607:CCT:C	acceptor_loss	1.0000
12:29518608:C:CC	acceptor_gain	1.0000
12:29518609:T:A	acceptor_loss	1.0000
12:29520613:CTTA:C	donor_loss	1.0000
12:29520614:TTACC:T	donor_loss	1.0000
12:29520615:TAC:T	donor_loss	1.0000

AlphaMissense

5738 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:29556962:C:T	G524E	1.000
12:29556967:G:C	N522K	1.000
12:29556967:G:T	N522K	1.000
12:29572159:A:G	L493P	1.000
12:29572168:G:T	A490D	1.000
12:29572173:G:C	N488K	1.000
12:29572173:G:T	N488K	1.000
12:29572185:C:A	K484N	1.000
12:29572185:C:G	K484N	1.000
12:29583432:A:G	W465R	1.000
12:29583432:A:T	W465R	1.000
12:29604210:A:C	F406L	1.000
12:29604210:A:T	F406L	1.000
12:29604212:A:G	F406L	1.000
12:29633263:A:G	W338R	1.000
12:29633263:A:T	W338R	1.000
12:29633265:T:A	D337V	1.000
12:29755781:T:A	E220V	1.000
12:29755783:T:A	K219N	1.000
12:29755783:T:G	K219N	1.000
12:29755784:T:A	K219I	1.000
12:29783487:G:C	H89D	1.000
12:29783515:C:A	W79C	1.000
12:29783515:C:G	W79C	1.000
12:29783517:A:G	W79R	1.000
12:29783517:A:T	W79R	1.000
12:29783518:G:C	F78L	1.000
12:29783518:G:T	F78L	1.000
12:29783520:A:G	F78L	1.000
12:29783594:T:A	D53V	1.000

dbSNP variants (sampled 300 via entrez): RS1000020101 (12:29768413 C>G,T), RS1000020839 (12:29720840 T>C), RS1000029919 (12:29768133 C>A,T), RS1000030110 (12:29500861 T>C), RS1000034584 (12:29726865 C>T), RS1000037695 (12:29614779 G>C), RS1000048447 (12:29572840 C>G,T), RS1000048875 (12:29751366 C>A,T), RS1000048939 (12:29696321 T>C), RS1000053684 (12:29614437 G>A), RS1000061059 (12:29542260 T>C), RS1000061426 (12:29686863 G>T), RS1000064831 (12:29623165 T>C), RS1000084777 (12:29542658 G>A,T), RS1000085659 (12:29622611 C>G)

Disease associations

OMIM: gene MIM:615855 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000675_4	Heart failure	3.000000e-06
GCST001657_7	Schizophrenia	7.000000e-06
GCST002539_14	Schizophrenia	4.000000e-08
GCST003209_8	Colorectal or endometrial cancer	1.000000e-07
GCST004946_97	Schizophrenia	2.000000e-11
GCST006134_7	Hippocampal volume	7.000000e-06
GCST006803_50	Schizophrenia	2.000000e-06
GCST007201_174	Schizophrenia	7.000000e-10
GCST007201_335	Schizophrenia	8.000000e-08
GCST009153_8	Adverse response to chemotherapy (amenorrhea) in breast cancer	1.000000e-06
GCST009819_3	Compulsion score in obsessive compulsive disorder	9.000000e-06
GCST010923_10	Beta blocker survival benefit in heart failure with reduced ejection fraction (time to all cause mortality x beta blocker interaction)	7.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004230	endometrial neoplasm
EFO:0005035	hippocampal volume
EFO:0007802	obsessive-compulsive symptom measurement
EFO:0004352	mortality
EFO:0007766	response to beta blocker

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	9
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Aflatoxin B1	affects expression, decreases expression	3
bisphenol A	increases expression, affects cotreatment, decreases expression	2
entinostat	affects cotreatment, decreases expression	2
Dexamethasone	affects cotreatment, decreases expression, increases expression	2
Doxorubicin	affects expression, increases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Indomethacin	decreases expression, affects cotreatment	2
Tretinoin	decreases expression	2
Cyclosporine	increases expression	2
urushiol	increases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
sodium arsenate	increases expression, increases abundance	1
arsenite	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	increases expression	1
homosalate	increases expression, increases reaction	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
NSC 689534	increases expression	1

Clinical trials (associated diseases)

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