TM4SF20

Summary

TM4SF20 (transmembrane 4 L six family member 20, HGNC:26230) is a protein-coding gene on chromosome 2q36.3, encoding Transmembrane 4 L6 family member 20 (Q53R12). Polytopic transmembrane protein that inhibits regulated intramembrane proteolysis (RIP) of CREB3L1, inhibiting its activation and the induction of collagen synthesis.

The protein encoded by this gene is a member of the four-transmembrane L6 superfamily. Members of this family function in various cellular processes including cell proliferation, motility, and adhesion via their interactions with integrins. In human brain tissue, this gene is expressed at high levels in the parietal lobe, occipital lobe, hippocampus, pons, white matter, corpus callosum, and cerebellum. Knockout of the homologous gene in mouse results in a neurobehavioral phenotype with suggested enhanced motor coordination. A deletion mutation in the human gene is associated with specific language impairment-5.

Source: NCBI Gene 79853 — RefSeq curated summary.

At a glance

• Gene–disease (curated): specific language impairment 5 (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 102 total — 2 pathogenic
• Phenotypes (HPO): 7
• MANE Select transcript: NM_024795

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26230
Approved symbol	TM4SF20
Name	transmembrane 4 L six family member 20
Location	2q36.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22800, TCCE518
Ensembl gene	ENSG00000168955
Ensembl biotype	protein_coding
OMIM	615404
Entrez	79853

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000304568, ENST00000449706

RefSeq mRNA: 1 — MANE Select: NM_024795 NM_024795

CCDS: CCDS2466

Canonical transcript exons

ENST00000304568 — 4 exons

Exon	Start	End
ENSE00001124101	227362038	227364012
ENSE00001124107	227379086	227379306
ENSE00001134324	227366093	227366244
ENSE00001134331	227370915	227370980

Expression profiles

Bgee: expression breadth broad, 77 present calls, max score 99.03.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5175 / max 691.2163, expressed in 65 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34345	1.1060	15
34346	0.2354	31
34347	0.1399	33
34348	0.0362	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.03	gold quality
ileal mucosa	UBERON:0000331	95.73	gold quality
ileum	UBERON:0002116	95.63	silver quality
duodenum	UBERON:0002114	95.48	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.32	gold quality
small intestine	UBERON:0002108	86.03	gold quality
pancreatic ductal cell	CL:0002079	77.39	silver quality
buccal mucosa cell	CL:0002336	76.53	gold quality
jejunum	UBERON:0002115	76.32	gold quality
rectum	UBERON:0001052	72.81	gold quality
mucosa of transverse colon	UBERON:0004991	70.15	gold quality
colonic mucosa	UBERON:0000317	65.28	gold quality
endothelial cell	CL:0000115	62.36	gold quality
intestine	UBERON:0000160	61.62	gold quality
amniotic fluid	UBERON:0000173	61.15	silver quality
mucosa of sigmoid colon	UBERON:0004993	61.10	silver quality
vena cava	UBERON:0004087	59.59	gold quality
oocyte	CL:0000023	59.45	gold quality
left testis	UBERON:0004533	58.42	gold quality
tendon of biceps brachii	UBERON:0008188	57.20	silver quality
transverse colon	UBERON:0001157	57.09	gold quality
testis	UBERON:0000473	56.93	gold quality
cerebellar vermis	UBERON:0004720	56.42	gold quality
right testis	UBERON:0004534	56.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	55.30	silver quality
epithelial cell of pancreas	CL:0000083	54.21	silver quality
smooth muscle tissue	UBERON:0001135	54.21	gold quality
cranial nerve II	UBERON:0000941	54.03	silver quality
islet of Langerhans	UBERON:0000006	53.41	gold quality
large intestine	UBERON:0000059	52.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	69.37
E-ANND-3	yes	7.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting TM4SF20, 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-3613-3P	100.00	76.36	7965
HSA-MIR-30D-5P	100.00	76.32	3233
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-30E-5P	100.00	76.32	3242
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-548O-3P	99.74	69.30	2228

Literature-anchored findings (GeneRIF, showing 4)

• TM4SF20 ancestral deletion predisposes carriers to a pediatric disorder of early language delay and cerebral white matter hyperintensities. (PMID:23810381)
• Ceramide inverts the membrane orientation of TMS4SF20, creating a form of TM4SF20 that stimulates the cleavage of CREB3L1. (PMID:27499293)
• TM4SF20 is the first protein shown to undergo Regulated Alternative Translocation in response to ceramide. In the absence of ceramide, the N terminus of the first transmembrane helix of TM4SF20 is inserted into the ER lumen. This form blocks activation of CREB3L1, a membrane-bound transcription factor. In the presence of ceramide, the membrane topology of TM4SF20 is inverted. The inverted form stimulates CREB3L1 cleavage. (PMID:27499293)
• Identification of residues critical for topology inversion of the transmembrane protein TM4SF20 through regulated alternative translocation. (PMID:30808712)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tm4sf20	ENSMUSG00000026149
rattus_norvegicus	Tm4sf20	ENSRNOG00000015460

Paralogs (5): TM4SF5 (ENSG00000142484), TM4SF19 (ENSG00000145107), TM4SF18 (ENSG00000163762), TM4SF4 (ENSG00000169903), TM4SF1 (ENSG00000169908)

Protein

Protein identifiers

Transmembrane 4 L6 family member 20 — Q53R12 (reviewed: Q53R12)

All UniProt accessions (2): Q53R12, C9JES4

UniProt curated annotations — full annotation on UniProt →

Function. Polytopic transmembrane protein that inhibits regulated intramembrane proteolysis (RIP) of CREB3L1, inhibiting its activation and the induction of collagen synthesis. In response to ceramide, which alters TM4SF20 membrane topology, stimulates RIP activation of CREB3L1. Ceramide reverses the direction through which transmembrane helices are translocated into the endoplasmic reticulum membrane during translation of TM4SF20, this mechanism is called ‘regulated alternative translocation’ (RAT) and regulates the function of the transmembrane protein.

Subcellular location. Membrane. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in the brain, with high levels in the parietal lobe, hippocampus, pons, white matter and cerebellum.

Post-translational modifications. Glycosylated at Asn-132, Asn-148 and Asn-163 in presence of ceramide which inverts the orientation of TM4SF20 in membranes exposing these residues to the endoplasmic reticulum lumen. Cleaved by signal peptidase at Ser-14 but the peptide does not act as a signal peptide. Cleavage is inhibited by ceramide which inverts the orientation of TM4SF20 in membranes exposing the N-terminus to the cytosol and not to the endoplasmic reticulum lumen.

Disease relevance. Specific language impairment 5 (SLI5) [MIM:615432] A disorder characterized by a delay in early speech acquisition. It is usually associated with cerebral white matter abnormalities on brain MRI. Some individuals may show disorders in communication, consistent with autism spectrum disorder, or global developmental delay, although others ultimately show normal cognitive function. Penetrance is incomplete and expressivity is variable. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The first transmembrane helix plays a critical role for the insertion orientation in the endoplasmic reticulum membrane.

Induction. TGFB1 inhibits TM4SF20 expression to activate CREB3L1.

Similarity. Belongs to the L6 tetraspanin family.

RefSeq proteins (1): NP_079071* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008661	L6_membrane	Family

Pfam: PF05805

UniProt features (24 total): mutagenesis site 11, topological domain 5, transmembrane region 4, chain 1, site 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53R12-F1	73.10	0.29

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 (1): 13–14 (cleavage)

Mutagenesis-validated functional residues (11):

Position	Phenotype
12	no effect on cleavage of the first 13 residues.
13	no effect on cleavage of the first 13 residues.
14	abolishes cleavage of the first 13 residues.
15	no effect on cleavage of the first 13 residues.
16	no effect on cleavage of the first 13 residues.
22	inverts transmembrane topology. induces cleavage of creb3l1.
26	inverts transmembrane topology.
80	no effect on glycosylation upon ceramide treatment.
132	reduces glycosylation upon ceramide treatment. abolishes glycosylation upon ceramide treatment; when associated with q-1
148	reduces glycosylation upon ceramide treatment. abolishes glycosylation upon ceramide treatment; when associated with q-1
163	reduces glycosylation upon ceramide treatment. abolishes glycosylation upon ceramide treatment; when associated with q-1

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 76 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, HNF1_01, RIGGI_EWING_SARCOMA_PROGENITOR_UP, GOBP_REGULATION_OF_PROTEOLYSIS, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOBP_PROTEOLYSIS, GOCC_ORGANELLE_SUBCOMPARTMENT, GOBP_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, VECCHI_GASTRIC_CANCER_ADVANCED_VS_EARLY_DN, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A, PRC1_BMI_UP.V1_DN, PRC2_SUZ12_UP.V1_DN, NOTCH_DN.V1_DN, NFE2L2.V2

GO Biological Process (1): negative regulation of proteolysis (GO:0045861)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), focal adhesion (GO:0005925), membrane (GO:0016020), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cell-substrate junction	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

394 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TM4SF20	TM4SF18	Q96CE8	608
TM4SF20	TM4SF19	Q96DZ7	528
TM4SF20	CREB3L1	Q96BA8	494
TM4SF20	TM4SF4	P48230	455
TM4SF20	IGSF23	A1L1A6	450
TM4SF20	TEX261	Q6UWH6	446
TM4SF20	TTC16	Q8NEE8	444
TM4SF20	GPA33	Q99795	441
TM4SF20	PLLP	Q9Y342	424
TM4SF20	ATP2C2	O75185	419
TM4SF20	TRAM1	Q15629	405
TM4SF20	NFXL1	Q6ZNB6	400
TM4SF20	LCN15	Q6UWW0	396
TM4SF20	ZNF232	Q9UNY5	393
TM4SF20	HNRNPK	P61978	393

IntAct

12 interactions, top by confidence:

A	B	Type	Score
TM4SF20	NINJ2	psi-mi:“MI:0915”(physical association)	0.560
VAMP3	TM4SF20	psi-mi:“MI:0915”(physical association)	0.560
BBS1	TM4SF20	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	TM4SF20	psi-mi:“MI:0915”(physical association)	0.370
TM4SF20	CD74	psi-mi:“MI:0914”(association)	0.350
TM4SF20	AK1	psi-mi:“MI:0914”(association)	0.350
NINJ2	TM4SF20	psi-mi:“MI:0915”(physical association)	0.000
VAMP3	TM4SF20	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): VKORC1L1 (Affinity Capture-MS), MBOAT7 (Affinity Capture-MS), HSDL1 (Affinity Capture-MS), TMEM186 (Affinity Capture-MS), CAB39 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), CD74 (Affinity Capture-MS), RHOA (Affinity Capture-MS), FAM210B (Affinity Capture-MS), CD74 (Affinity Capture-MS), FAM210B (Affinity Capture-MS), HSDL1 (Affinity Capture-MS), TMEM186 (Affinity Capture-MS), MBOAT7 (Affinity Capture-MS), C10orf35 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8RY99, A0PK11, A9UL59, B2RVW2, B4L184, B4LC58, B4N5D3, D3ZFW5, O95473, P23290, P35801, P35802, P35803, P36964, P36965, P51674, P56749, P58418, P79826, Q0IIL2, Q0P4G7, Q0VD07, Q11085, Q13491, Q2YDD6, Q53R12, Q5R603, Q5R9K1, Q5R9Q3, Q5R9R3, Q5T9L3, Q5ZLR1, Q6AYR5, Q6CRM6, Q6DID7, Q6P689, Q6UX40, Q754N9, Q7YWX7, Q812E9

Diamond homologs: E9Q9H8, O14894, P30408, P48230, P49111, Q2KIG8, Q3T110, Q53R12, Q5R6Z4, Q5RE43, Q64302, Q91XD3, Q96CE8, Q96DZ7, Q9CQY8, Q9EQL5, Q3T0Z4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	66
Likely benign	23
Benign	9

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
243063	TM4SF20, 4-KB DEL	Pathogenic
625778	GRCh37/hg19 2q36.3(chr2:228230759-228234864)	Pathogenic

SpliceAI

419 predictions. Top by Δscore:

Variant	Effect	Δscore
2:227364008:TGTCA:T	acceptor_gain	1.0000
2:227364009:GTCA:G	acceptor_gain	1.0000
2:227364010:TCA:T	acceptor_gain	1.0000
2:227364011:CA:C	acceptor_gain	1.0000
2:227364011:CAC:C	acceptor_gain	1.0000
2:227364012:ACTG:A	acceptor_loss	1.0000
2:227364013:C:CC	acceptor_gain	1.0000
2:227364013:CT:C	acceptor_loss	1.0000
2:227364014:T:G	acceptor_loss	1.0000
2:227370913:A:AC	donor_gain	1.0000
2:227370913:ACT:A	donor_gain	1.0000
2:227370914:C:CC	donor_gain	1.0000
2:227370914:CTC:C	donor_gain	1.0000
2:227370981:C:CC	acceptor_gain	1.0000
2:227379159:T:TA	donor_gain	1.0000
2:227366087:ACTT:A	donor_loss	0.9900
2:227366088:CTT:C	donor_loss	0.9900
2:227366089:TTA:T	donor_loss	0.9900
2:227366090:TACCT:T	donor_loss	0.9900
2:227366091:A:AC	donor_gain	0.9900
2:227366092:C:CC	donor_gain	0.9900
2:227366220:CA:C	acceptor_gain	0.9900
2:227366222:C:CC	acceptor_gain	0.9900
2:227366242:CAT:C	acceptor_gain	0.9900
2:227370914:CT:C	donor_gain	0.9900
2:227370977:TGGC:T	acceptor_gain	0.9900
2:227370979:GCCT:G	acceptor_loss	0.9900
2:227370981:CTGG:C	acceptor_loss	0.9900
2:227379199:C:CT	donor_gain	0.9900
2:227379200:T:TT	donor_gain	0.9900

AlphaMissense

1511 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:227366191:G:C	C101W	0.990
2:227363790:A:C	S208R	0.988
2:227363790:A:T	S208R	0.988
2:227363792:T:G	S208R	0.988
2:227366160:C:A	G112C	0.987
2:227363838:A:C	F192L	0.986
2:227363838:A:T	F192L	0.986
2:227363840:A:G	F192L	0.986
2:227363979:C:A	W145C	0.983
2:227363979:C:G	W145C	0.983
2:227366204:C:T	G97D	0.983
2:227366221:A:C	S91R	0.981
2:227366221:A:T	S91R	0.981
2:227366223:T:G	S91R	0.981
2:227379191:A:C	N26K	0.981
2:227379191:A:T	N26K	0.981
2:227366193:A:G	C101R	0.977
2:227366180:G:A	S105F	0.976
2:227366160:C:G	G112R	0.975
2:227379093:C:T	G59D	0.975
2:227363819:C:G	G199R	0.973
2:227363819:C:T	G199R	0.973
2:227363830:A:G	L195P	0.971
2:227366180:G:T	S105Y	0.971
2:227366192:C:T	C101Y	0.971
2:227366205:C:G	G97R	0.970
2:227379109:C:G	G54R	0.970
2:227379109:C:T	G54R	0.970
2:227379205:C:G	G22R	0.969
2:227379205:C:T	G22R	0.969

dbSNP variants (sampled 300 via entrez): RS1000020956 (2:227371545 G>A,C), RS1000116361 (2:227375674 A>G), RS1000154586 (2:227375527 T>C), RS1000344491 (2:227380843 C>T), RS1000446544 (2:227375226 CA>C,CAA), RS1000594296 (2:227363329 C>A,T), RS1000608415 (2:227362436 TGAG>T), RS1000626821 (2:227370281 G>A), RS1001143758 (2:227369979 A>T), RS1001257645 (2:227379874 A>T), RS1001384289 (2:227364391 C>T), RS1001440617 (2:227374376 C>T), RS1001562537 (2:227368293 G>A), RS1001825587 (2:227361706 T>G), RS1001886225 (2:227375894 C>G,T)

Disease associations

OMIM: gene MIM:615404 | disease phenotypes: MIM:615432

GenCC curated gene-disease

Disease	Classification	Inheritance
specific language impairment 5	Limited	Autosomal dominant

Mondo (1): specific language impairment 5 (MONDO:0014184)

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001263	Global developmental delay
HP:0002463	Language impairment
HP:0003829	Typified by incomplete penetrance
HP:0030890	Hyperintensity of cerebral white matter on MRI

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007465_2	Phoneme awareness	9.000000e-06
GCST011742_42	Triglyceride levels in HIV infection	5.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005301	reading and spelling ability
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	decreases expression	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
incobotulinumtoxinA	increases expression	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Daunorubicin	affects response to substance	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Methotrexate	decreases expression	1
Silicon Dioxide	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Asbestos, Crocidolite	decreases expression	1
Okadaic Acid	affects expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

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