TMEFF1

Summary

TMEFF1 (transmembrane protein with EGF like and two follistatin like domains 1, HGNC:11866) is a protein-coding gene on chromosome 9q31.1, encoding Tomoregulin-1 (Q8IYR6). Neuron-specific restriction factor that prevents herpes simplex virus 1 (HHV-1) infection in the brain by blocking viral entry.

Enables receptor ligand inhibitor activity. Involved in host-mediated suppression of symbiont invasion. Is active in plasma membrane.

Source: NCBI Gene 8577 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary predisposition to infections (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 3 total
• MANE Select transcript: NM_003692

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11866
Approved symbol	TMEFF1
Name	transmembrane protein with EGF like and two follistatin like domains 1
Location	9q31.1
Locus type	gene with protein product
Status	Approved
Aliases	H7365, CT120.1
Ensembl gene	ENSG00000241697
Ensembl biotype	protein_coding
OMIM	603421
Entrez	8577

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000374879, ENST00000906121, ENST00000906122, ENST00000906123, ENST00000906124, ENST00000921423, ENST00000921424, ENST00000921425, ENST00000943592

RefSeq mRNA: 1 — MANE Select: NM_003692 NM_003692

CCDS: CCDS6750

Canonical transcript exons

ENST00000374879 — 10 exons

Exon	Start	End
ENSE00001464986	100473149	100473740
ENSE00003478392	100576516	100577636
ENSE00003486512	100516675	100516771
ENSE00003539108	100498765	100498874
ENSE00003555295	100550095	100550160
ENSE00003565104	100572518	100572676
ENSE00003566709	100513307	100513333
ENSE00003630422	100509005	100509134
ENSE00003674678	100561397	100561520
ENSE00003690723	100547744	100547892

Expression profiles

Bgee: expression breadth broad, 86 present calls, max score 89.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.7946 / max 296.0451, expressed in 957 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
97725	2.7785	440
97720	2.7352	747
97722	2.1257	335
97721	1.5920	406
97724	0.2302	95
97726	0.2176	101
97723	0.1152	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	89.22	gold quality
ganglionic eminence	UBERON:0004023	88.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.36	gold quality
ventricular zone	UBERON:0003053	79.78	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	79.76	gold quality
corpus callosum	UBERON:0002336	78.15	gold quality
superior frontal gyrus	UBERON:0002661	77.29	gold quality
primary visual cortex	UBERON:0002436	75.47	gold quality
substantia nigra	UBERON:0002038	74.47	gold quality
putamen	UBERON:0001874	74.44	gold quality
Brodmann (1909) area 9	UBERON:0013540	73.36	gold quality
hypothalamus	UBERON:0001898	73.21	gold quality
Ammon’s horn	UBERON:0001954	73.06	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	71.90	gold quality
cerebral cortex	UBERON:0000956	70.67	gold quality
caudate nucleus	UBERON:0001873	70.44	gold quality
nucleus accumbens	UBERON:0001882	69.63	gold quality
anterior cingulate cortex	UBERON:0009835	69.45	gold quality
prefrontal cortex	UBERON:0000451	69.40	gold quality
temporal lobe	UBERON:0001871	68.70	gold quality
frontal cortex	UBERON:0001870	68.47	gold quality
amygdala	UBERON:0001876	68.45	gold quality
stromal cell of endometrium	CL:0002255	68.04	gold quality
brain	UBERON:0000955	65.41	gold quality
right frontal lobe	UBERON:0002810	65.22	gold quality
endometrium	UBERON:0001295	63.26	gold quality
right testis	UBERON:0004534	55.81	gold quality
testis	UBERON:0000473	55.71	gold quality
left testis	UBERON:0004533	55.57	gold quality
left lobe of thyroid gland	UBERON:0001120	52.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	8.09
E-ANND-3	no	0.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

134 targeting TMEFF1, 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-4262	100.00	73.26	3931
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
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-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910

Literature-anchored findings (GeneRIF, showing 6)

• This protein may behave as a tumor suppressor gene in brain cancers. (PMID:12743596)
• In Xenopus, TMEFF1 blocks nodal signaling through binding to the nodal coreceptor Cripto; it does not associate with either nodal or the type I activin receptor-like kinase (ALK) 4 receptor. (PMID:14563676)
• Interaction between TMEFF1 and AHNAK proteins in ovarian cancer cells: Implications for clinical prognosis. (PMID:35338959)
• MIR503HG impeded ovarian cancer progression by interacting with SPI1 and preventing TMEFF1 transcription. (PMID:35771155)
• TMEFF1 is a neuron-specific restriction factor for herpes simplex virus. (PMID:39048823)
• Human TMEFF1 is a restriction factor for herpes simplex virus in the brain. (PMID:39048830)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tmeff1	ENSMUSG00000028347
rattus_norvegicus	Tmeff1	ENSRNOG00000008034

Paralogs (27): USH2A (ENSG00000042781), LAMC3 (ENSG00000050555), LAMA3 (ENSG00000053747), LAMC2 (ENSG00000058085), NTN1 (ENSG00000065320), NTN4 (ENSG00000074527), ATRN (ENSG00000088812), LAMB4 (ENSG00000091128), LAMB1 (ENSG00000091136), LAMA1 (ENSG00000101680), MEGF8 (ENSG00000105429), MEGF9 (ENSG00000106780), ATRNL1 (ENSG00000107518), LAMA4 (ENSG00000112769), LAMA5 (ENSG00000130702), LAMC1 (ENSG00000135862), NTN5 (ENSG00000142233), HSPG2 (ENSG00000142798), TMEFF2 (ENSG00000144339), NTN3 (ENSG00000162068), NTNG1 (ENSG00000162631), EGFLAM (ENSG00000164318), LAMB2 (ENSG00000172037), AGRN (ENSG00000188157), NTNG2 (ENSG00000196358), LAMA2 (ENSG00000196569), LAMB3 (ENSG00000196878)

Protein

Protein identifiers

Tomoregulin-1 — Q8IYR6 (reviewed: Q8IYR6)

Alternative names: H7365, Transmembrane protein with EGF-like and one follistatin-like domain

All UniProt accessions (1): Q8IYR6

UniProt curated annotations — full annotation on UniProt →

Function. Neuron-specific restriction factor that prevents herpes simplex virus 1 (HHV-1) infection in the brain by blocking viral entry. Also able to restrict herpes simplex virus 2 (HHV-2) infection, although to a lesser extent. Acts by preventing the association between the viral glycoprotein D (gD) and its cell surface receptor NECTIN1, thereby inhibiting fusion of the virus and the cell membrane. Also able to prevent the association between the viral glycoprotein B (gB) and MYH9/NMMHC-IIA and MYH10/NMMHC-IIB receptors. May be a tumor suppressor in brain cancers.

Subunit / interactions. May interact with ST14.

Subcellular location. Cell membrane.

Tissue specificity. Expressed predominantly in brain, and at lower levels in heart, placenta and skeletal muscle. Down-regulated in brain tumors as compared to control brain tissues.

Disease relevance. Encephalopathy, acute, infection-induced, herpes-specific (IIAE). A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the tomoregulin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IYR6-1	1	yes
Q8IYR6-2	2

RefSeq proteins (1): NP_003683* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR002350	Kazal_dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily

Pfam: PF07648

UniProt features (28 total): disulfide bond 9, sequence conflict 4, domain 3, site 2, topological domain 2, sequence variant 2, signal peptide 1, chain 1, splice variant 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYR6-F1	69.30	0.20

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): 105–106 (reactive bond); 196–197 (reactive bond)

Disulfide bonds (9): 99–129, 103–122, 111–143, 190–221, 194–214, 203–235, 275–288, 283–299, 301–310

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 183 (showing top): BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, TGACCTY_ERR1_Q2, DAVICIONI_RHABDOMYOSARCOMA_PAX_FOXO1_FUSION_UP, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, SOX9_B1, PPAR_DR1_Q2, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_HOST_MEDIATED_SUPPRESSION_OF_SYMBIONT_INVASION, AACTTT_UNKNOWN, RYTTCCTG_ETS2_B, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, DOUGLAS_BMI1_TARGETS_UP, TGGAAA_NFAT_Q4_01, CAIRO_LIVER_DEVELOPMENT_UP

GO Biological Process (2): host-mediated suppression of symbiont invasion (GO:0046597), symbiont entry into host cell (GO:0046718)

GO Molecular Function (2): receptor ligand inhibitor activity (GO:0141069), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
innate immune response	1
host-mediated perturbation of symbiont process	1
viral life cycle	1
symbiont entry into host	1
receptor ligand activity	1
molecular function inhibitor activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

446 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEFF1	CRIPTO	P13385	689
TMEFF1	EGF	P01133	566
TMEFF1	ERVFRD-1	P60508	436
TMEFF1	ERV3-1	Q14264	436
TMEFF1	H0YJ60	H0YJ60	420
TMEFF1	FST	P19883	417
TMEFF1	SNAI3	Q3KNW1	355
TMEFF1	ERVW-1	Q9UQF0	350
TMEFF1	SMAD2	Q15796	329
TMEFF1	TGFB2	P08112	324
TMEFF1	C9orf72	Q96LT7	323
TMEFF1	TSPAN13	O95857	311
TMEFF1	ACVR1B	P36896	309
TMEFF1	GNG11	P50152	303
TMEFF1	TMEM132A	Q24JP5	294

IntAct

27 interactions, top by confidence:

A	B	Type	Score
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
GPR183	NRP1	psi-mi:“MI:0914”(association)	0.530
PDPK1	AGRN	psi-mi:“MI:0914”(association)	0.530
HADHA	AGRN	psi-mi:“MI:0914”(association)	0.530
TMEFF1	CCR1	psi-mi:“MI:0915”(physical association)	0.370
APC	TMEFF1	psi-mi:“MI:0915”(physical association)	0.370
BUB1	TMEFF1	psi-mi:“MI:0915”(physical association)	0.370
CDKN2A	TMEFF1	psi-mi:“MI:0915”(physical association)	0.370
TMEFF1	DLC1	psi-mi:“MI:0915”(physical association)	0.370
FLCN	TMEFF1	psi-mi:“MI:0915”(physical association)	0.370
MLH3	TMEFF1	psi-mi:“MI:0915”(physical association)	0.370
TMEFF1	PTEN	psi-mi:“MI:0915”(physical association)	0.370
PTPRJ	TMEFF1	psi-mi:“MI:0915”(physical association)	0.370
TMEFF1	FGF2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	IGLON5	psi-mi:“MI:0914”(association)	0.350
TMEFF1	MAP7D3	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TMEFF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (62): TMEFF1 (Affinity Capture-MS), SLC39A11 (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), STEAP3 (Affinity Capture-MS), FGF2 (Affinity Capture-MS), HADHB (Affinity Capture-MS), EXOC1 (Affinity Capture-MS), ZDHHC5 (Affinity Capture-MS), ATP2C1 (Affinity Capture-MS), PRDM10 (Affinity Capture-MS), BCS1L (Affinity Capture-MS), METTL9 (Affinity Capture-MS), INTS7 (Affinity Capture-MS), GOLGA7 (Affinity Capture-MS), THNSL1 (Affinity Capture-MS)

ESM2 similar proteins: A1XQX1, A1XQX3, A1XQY0, A8WGA3, C6K2K4, D0PRN2, D0PRN4, D4A1J9, E9PUN2, O13097, O42596, O73612, O73874, P0DI97, P52795, P52796, P58400, P58401, P98172, Q01974, Q0PMD2, Q17QD6, Q28142, Q28143, Q460M5, Q63373, Q63376, Q6NW40, Q6PCX7, Q6PFE7, Q7TQ33, Q80TG9, Q8BNJ6, Q8BXA0, Q8C985, Q8IYR6, Q8NC67, Q91590, Q96B86, Q96NI6

Diamond homologs: A0A1D5PUP4, A0JP86, A2ASQ1, A3KN33, A5YT95, E9Q7X7, G4V4G1, G5ECE3, O00468, O00634, O09118, O15230, O62650, O75094, O75445, O88280, O94813, O95631, O95633, O95980, P02468, P02469, P07942, P0DKM7, P0DKM8, P0DKM9, P10184, P10669, P11046, P11047, P15215, P15800, P16895, P19883, P21674, P25304, P31514, P31515, P31696, P47931

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

2314 predictions. Top by Δscore:

Variant	Effect	Δscore
9:100498759:TTGCA:T	acceptor_loss	1.0000
9:100498760:TGCAG:T	acceptor_loss	1.0000
9:100498761:GCA:G	acceptor_loss	1.0000
9:100498761:GCAG:G	acceptor_loss	1.0000
9:100498762:CAGA:C	acceptor_loss	1.0000
9:100498763:A:AG	acceptor_gain	1.0000
9:100498763:A:C	acceptor_loss	1.0000
9:100498764:G:A	acceptor_loss	1.0000
9:100498764:G:GG	acceptor_gain	1.0000
9:100498764:GA:G	acceptor_gain	1.0000
9:100498764:GAA:G	acceptor_gain	1.0000
9:100498764:GAATT:G	acceptor_gain	1.0000
9:100498871:TCAG:T	donor_loss	1.0000
9:100498871:TCAGG:T	donor_loss	1.0000
9:100498872:CAGG:C	donor_loss	1.0000
9:100498873:AGG:A	donor_loss	1.0000
9:100498873:AGGT:A	donor_loss	1.0000
9:100498874:GG:G	donor_loss	1.0000
9:100498875:GT:G	donor_loss	1.0000
9:100498876:T:A	donor_loss	1.0000
9:100498876:T:G	donor_loss	1.0000
9:100509003:A:AG	acceptor_gain	1.0000
9:100509004:G:GA	acceptor_gain	1.0000
9:100509004:GT:G	acceptor_gain	1.0000
9:100509004:GTGC:G	acceptor_gain	1.0000
9:100509004:GTGCC:G	acceptor_gain	1.0000
9:100509131:TCTGG:T	donor_loss	1.0000
9:100509132:CTGG:C	donor_loss	1.0000
9:100509135:G:A	donor_loss	1.0000
9:100509135:G:GC	donor_loss	1.0000

AlphaMissense

2496 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:100498812:T:A	C82S	1.000
9:100498813:G:C	C82S	1.000
9:100509005:T:A	C103S	1.000
9:100509005:T:C	C103R	1.000
9:100509006:G:C	C103S	1.000
9:100509062:T:A	C122S	1.000
9:100509062:T:C	C122R	1.000
9:100509063:G:C	C122S	1.000
9:100509064:C:G	C122W	1.000
9:100509083:T:A	C129S	1.000
9:100509083:T:C	C129R	1.000
9:100509084:G:A	C129Y	1.000
9:100509084:G:C	C129S	1.000
9:100509085:T:G	C129W	1.000
9:100516746:T:A	C179S	1.000
9:100516747:G:C	C179S	1.000
9:100547751:T:A	C190S	1.000
9:100547751:T:C	C190R	1.000
9:100547752:G:A	C190Y	1.000
9:100547752:G:C	C190S	1.000
9:100547763:T:A	C194S	1.000
9:100547763:T:C	C194R	1.000
9:100547764:G:A	C194Y	1.000
9:100547764:G:C	C194S	1.000
9:100547765:C:G	C194W	1.000
9:100547790:T:A	C203S	1.000
9:100547790:T:C	C203R	1.000
9:100547791:G:C	C203S	1.000
9:100547823:T:A	C214S	1.000
9:100547823:T:C	C214R	1.000

dbSNP variants (sampled 300 via entrez): RS1000069793 (9:100504598 A>G), RS1000069916 (9:100533281 C>G), RS1000076640 (9:100534356 A>T), RS1000138297 (9:100497623 G>A,T), RS1000190236 (9:100566065 C>T), RS1000223602 (9:100519564 C>A,T), RS1000238351 (9:100476145 G>A), RS1000241200 (9:100566331 A>G), RS1000264142 (9:100491190 T>C), RS1000280202 (9:100532611 G>A,T), RS1000396326 (9:100482002 G>A), RS1000477 (9:100511487 A>G,T), RS1000478 (9:100511121 T>C), RS1000479 (9:100510956 A>T), RS1000484764 (9:100566755 A>C)

Disease associations

OMIM: gene MIM:603421 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary predisposition to infections	Strong	Autosomal recessive

Mondo (1): (MONDO:0015979)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006088_17	Familial squamous cell lung carcinoma	3.000000e-06
GCST90011899_2	Aspartate aminotransferase levels	4.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006953	family history of lung cancer
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression	3
Valproic Acid	affects expression, decreases expression, decreases methylation	3
cobaltous chloride	decreases expression, increases expression	2
Cyclosporine	increases expression	2
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases expression	1
afimoxifene	decreases expression, decreases reaction	1
sodium arsenite	increases abundance, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
indeno(1,2,3-cd)pyrene	decreases expression	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	increases expression, affects cotreatment	1
jinfukang	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Arsenic	increases abundance, increases expression	1
Cyclophosphamide	affects response to substance	1
Estradiol	increases expression	1
Estrogens	decreases expression, decreases reaction	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Methotrexate	affects response to substance	1
Nickel	increases expression	1
Quercetin	increases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1
Coal Ash	decreases expression	1

Clinical trials (associated diseases)

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