TMEM53

Summary

TMEM53 (transmembrane protein 53, HGNC:26186) is a protein-coding gene on chromosome 1p34.1, encoding Transmembrane protein 53 (Q6P2H8). Ensures normal bone formation, through the negative regulation of bone morphogenetic protein (BMP) signaling in osteoblast lineage cells by blocking cytoplasm-nucleus translocation of phosphorylated SMAD1/5/9 proteins.

Involved in negative regulation of BMP signaling pathway; negative regulation of ossification; and regulation of nucleocytoplasmic transport. Located in nuclear membrane. Implicated in craniotubular dysplasia Ikegawa type.

Source: NCBI Gene 79639 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniotubular dysplasia, Ikegawa type (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 53 total — 1 pathogenic
• Phenotypes (HPO): 41
• MANE Select transcript: NM_024587

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26186
Approved symbol	TMEM53
Name	transmembrane protein 53
Location	1p34.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22353, NET4
Ensembl gene	ENSG00000126106
Ensembl biotype	protein_coding
OMIM	619722
Entrez	79639

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000372235, ENST00000372237, ENST00000372242, ENST00000372243, ENST00000372244, ENST00000420706, ENST00000468117, ENST00000476724, ENST00000495630

RefSeq mRNA: 4 — MANE Select: NM_024587 NM_001300746, NM_001300747, NM_001300748, NM_024587

CCDS: CCDS511, CCDS72773

Canonical transcript exons

ENST00000372237 — 3 exons

Exon	Start	End
ENSE00001145451	44660174	44660295
ENSE00001834248	44674331	44674481
ENSE00003492927	44653247	44655209

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 91.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3071 / max 82.3588, expressed in 1721 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12083	6.8094	1711
12082	0.2479	92
12084	0.1907	71
12081	0.0591	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	91.82	gold quality
mucosa of transverse colon	UBERON:0004991	91.06	gold quality
sperm	CL:0000019	90.51	gold quality
liver	UBERON:0002107	88.56	gold quality
left testis	UBERON:0004533	88.43	gold quality
right testis	UBERON:0004534	88.04	gold quality
male germ cell	CL:0000015	87.85	gold quality
pancreatic ductal cell	CL:0002079	86.69	silver quality
testis	UBERON:0000473	86.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.19	gold quality
epithelium of nasopharynx	UBERON:0001951	85.21	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.34	gold quality
apex of heart	UBERON:0002098	83.92	gold quality
prefrontal cortex	UBERON:0000451	83.75	gold quality
oocyte	CL:0000023	83.67	gold quality
transverse colon	UBERON:0001157	83.44	gold quality
right adrenal gland	UBERON:0001233	83.07	gold quality
heart left ventricle	UBERON:0002084	82.60	gold quality
adult mammalian kidney	UBERON:0000082	82.55	gold quality
cardiac ventricle	UBERON:0002082	82.18	gold quality
right atrium auricular region	UBERON:0006631	82.17	gold quality
nephron tubule	UBERON:0001231	82.05	silver quality
duodenum	UBERON:0002114	82.04	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	81.97	gold quality
left adrenal gland	UBERON:0001234	81.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.83	gold quality
right adrenal gland cortex	UBERON:0035827	81.82	gold quality
left adrenal gland cortex	UBERON:0035825	81.02	gold quality
small intestine	UBERON:0002108	80.87	gold quality
omental fat pad	UBERON:0010414	80.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.15
E-GEOD-110499	no	62.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

50 targeting TMEM53, 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-4673	100.00	66.64	1490
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-657	99.48	66.02	848
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-143-5P	98.98	68.87	946

Literature-anchored findings (GeneRIF, showing 1)

• Deficiency of TMEM53 causes a previously unknown sclerosing bone disorder by dysregulation of BMP-SMAD signaling. (PMID:33824347)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem53	ENSDARG00000038789
mus_musculus	Tmem53	ENSMUSG00000048772
rattus_norvegicus	Tmem53	ENSRNOG00000019186
drosophila_melanogaster	CG8245	FBGN0033031
caenorhabditis_elegans		WBGENE00012002
caenorhabditis_elegans		WBGENE00015623
caenorhabditis_elegans	T10B11.5	WBGENE00020401
caenorhabditis_elegans	T10B11.6	WBGENE00020402

Protein

Protein identifiers

Transmembrane protein 53 — Q6P2H8 (reviewed: Q6P2H8)

Alternative names: Nuclear envelope transmembrane protein 4

All UniProt accessions (6): Q6P2H8, Q5TDE2, Q5TDE3, Q5TDE4, Q5TDE5, Q5TDE6

UniProt curated annotations — full annotation on UniProt →

Function. Ensures normal bone formation, through the negative regulation of bone morphogenetic protein (BMP) signaling in osteoblast lineage cells by blocking cytoplasm-nucleus translocation of phosphorylated SMAD1/5/9 proteins.

Subcellular location. Nucleus outer membrane.

Tissue specificity. Widely expressed.

Disease relevance. Craniotubular dysplasia, Ikegawa type (CTDI) [MIM:619727] An autosomal recessive, sclerosing bone disorder characterized by proportional or short-limbed short stature in association with macrocephaly, dolichocephaly, or prominent forehead. Radiography shows hyperostosis of the calvaria and skull base, with metadiaphyseal undermodeling of the long tubular bones and mild shortening and diaphyseal broadening of the short tubular bones. Affected individuals experience progressive vision loss in the first decade of life due to optic nerve compression, and deafness may develop in the second decade of life. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TMEM53 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6P2H8-1	1, T.1	yes
Q6P2H8-2	2, T.2

RefSeq proteins (4): NP_001287675, NP_001287676, NP_001287677, NP_078863* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008547	DUF829_TMEM53	Family
IPR029058	AB_hydrolase_fold	Homologous_superfamily

Pfam: PF05705

UniProt features (5 total): sequence conflict 2, chain 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P2H8-F1	89.97	0.77

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 217 (showing top): AHRARNT_01, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_OSTEOBLAST_DIFFERENTIATION, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOBP_NUCLEAR_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_REGULATION_OF_NUCLEOCYTOPLASMIC_TRANSPORT, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, chr1p34, GOBP_NEGATIVE_REGULATION_OF_BMP_SIGNALING_PATHWAY, CYTAGCAAY_UNKNOWN, GOBP_OSSIFICATION, GOBP_RESPONSE_TO_BMP

GO Biological Process (4): negative regulation of ossification (GO:0030279), negative regulation of BMP signaling pathway (GO:0030514), negative regulation of osteoblast differentiation (GO:0045668), regulation of nucleocytoplasmic transport (GO:0046822)

GO Molecular Function (0):

GO Cellular Component (5): nucleus (GO:0005634), nuclear outer membrane (GO:0005640), nuclear membrane (GO:0031965), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
ossification	1
regulation of ossification	1
negative regulation of multicellular organismal process	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
osteoblast differentiation	1
negative regulation of cell differentiation	1
regulation of osteoblast differentiation	1
nucleocytoplasmic transport	1
regulation of intracellular transport	1
intracellular membrane-bounded organelle	1
nuclear membrane	1
organelle outer membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
nucleus	1
nuclear envelope	1
organelle membrane	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

368 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM53	RNF220	Q5VTB9	597
TMEM53	TMEM223	A0PJW6	591
TMEM53	ASPHD2	Q6ICH7	576
TMEM53	TMEM147	Q9BVK8	556
TMEM53	TMEM238	C9JI98	549
TMEM53	ACBD6	Q9BR61	549
TMEM53	ERI3	O43414	534
TMEM53	TMEM209	Q96SK2	505
TMEM53	RBM28	Q9NW13	496
TMEM53	B3GLCT	Q6Y288	490
TMEM53	NME7	Q9Y5B8	488
TMEM53	ARMH1	Q6PIY5	479
TMEM53	TMEM154	Q6P9G4	473
TMEM53	TMEM38A	Q9H6F2	461
TMEM53	TMUB1	Q9BVT8	461

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TMEM53	NME2P1	psi-mi:“MI:0915”(physical association)	0.400
EVA1B	C2CD2L	psi-mi:“MI:0914”(association)	0.350
TMEM53	RP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): NME2P1 (Affinity Capture-MS), TMEM53 (Affinity Capture-RNA), TMEM53 (Proximity Label-MS), TMEM53 (Proximity Label-MS), TMEM53 (Proximity Label-MS), TMEM53 (Affinity Capture-MS), NME2P1 (Affinity Capture-MS), DHX32 (Affinity Capture-MS), ATP6V0D2 (Affinity Capture-MS), PRKCA (Affinity Capture-MS), CCNB2 (Affinity Capture-MS), RP2 (Affinity Capture-MS), FLOT1 (Affinity Capture-MS), FLOT2 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A1A4L8, A1A4Q9, A1L134, A2BDX3, A5YM72, A6H707, B0BLZ5, B0JZP3, G3MZR2, O43292, O60831, O89109, P70295, Q11130, Q2TBP5, Q2V8X7, Q32NY4, Q3UPE3, Q4R4E4, Q4R4I9, Q5XIE1, Q5ZIW1, Q66HR0, Q6IQX7, Q6NRK8, Q6P2H8, Q7L1V2, Q80ZW2, Q86VU5, Q8IZ52, Q8N3Y3, Q8NE01, Q8NF37, Q8NI29, Q8TAC2, Q8TCD5, Q8TD43, Q8WUY1, Q92839, Q96DE0

Diamond homologs: Q2TBP5, Q5PPS7, Q6DHN0, Q6DJC8, Q6P2H8, Q9D0Z3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	46
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
986737	NM_024587.4(TMEM53):c.219_222dup (p.Val75fs)	Pathogenic

SpliceAI

1936 predictions. Top by Δscore:

Variant	Effect	Δscore
1:44635529:C:A	acceptor_gain	1.0000
1:44636029:GA:G	acceptor_gain	1.0000
1:44636099:GAGTA:G	donor_gain	1.0000
1:44644780:G:GG	donor_gain	1.0000
1:44644786:G:GT	donor_gain	1.0000
1:44644786:G:T	donor_gain	1.0000
1:44644795:G:GG	donor_gain	1.0000
1:44645219:A:AG	acceptor_gain	1.0000
1:44645219:AGT:A	acceptor_gain	1.0000
1:44645220:G:GA	acceptor_gain	1.0000
1:44645220:GTG:G	acceptor_gain	1.0000
1:44645484:GAGAA:G	donor_gain	1.0000
1:44645485:AGAA:A	donor_gain	1.0000
1:44645485:AGAAG:A	donor_loss	1.0000
1:44645486:GAA:G	donor_gain	1.0000
1:44645486:GAAG:G	donor_gain	1.0000
1:44645487:AA:A	donor_gain	1.0000
1:44645487:AAG:A	donor_loss	1.0000
1:44645488:AG:A	donor_loss	1.0000
1:44645489:G:GG	donor_gain	1.0000
1:44645490:T:A	donor_loss	1.0000
1:44649658:C:G	acceptor_gain	1.0000
1:44649658:CAGA:C	acceptor_loss	1.0000
1:44649659:A:AG	acceptor_gain	1.0000
1:44649659:AGAA:A	acceptor_loss	1.0000
1:44649660:G:GT	acceptor_gain	1.0000
1:44649660:GA:G	acceptor_gain	1.0000
1:44649660:GAA:G	acceptor_gain	1.0000
1:44649660:GAAT:G	acceptor_gain	1.0000
1:44649660:GAATC:G	acceptor_gain	1.0000

AlphaMissense

1784 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:44655055:C:A	S113I	0.997
1:44655054:G:C	S113R	0.994
1:44655054:G:T	S113R	0.994
1:44655056:T:G	S113R	0.994
1:44660228:C:A	W43C	0.994
1:44660228:C:G	W43C	0.994
1:44660230:A:G	W43R	0.994
1:44660230:A:T	W43R	0.994
1:44655055:C:T	S113N	0.991
1:44654961:G:C	S144R	0.989
1:44654961:G:T	S144R	0.989
1:44654963:T:G	S144R	0.989
1:44660219:G:C	C46W	0.987
1:44654965:T:A	D143V	0.986
1:44654965:T:C	D143G	0.986
1:44654977:C:T	G139D	0.986
1:44660233:C:G	G42R	0.986
1:44654583:G:C	F270L	0.985
1:44654583:G:T	F270L	0.985
1:44654585:A:G	F270L	0.985
1:44654630:G:C	H255D	0.985
1:44654637:G:C	H252Q	0.985
1:44654637:G:T	H252Q	0.985
1:44654734:T:A	D220V	0.985
1:44654965:T:G	D143A	0.985
1:44654652:G:C	F247L	0.984
1:44654652:G:T	F247L	0.984
1:44654653:A:G	F247S	0.984
1:44654654:A:G	F247L	0.984
1:44654744:A:G	S217P	0.984

dbSNP variants (sampled 300 via entrez): RS1000080023 (1:44659819 A>C), RS1000209403 (1:44667377 G>A), RS1000220849 (1:44655865 C>T), RS1000266514 (1:44675785 C>A), RS1000303027 (1:44669668 C>T), RS1000405029 (1:44662231 G>A), RS1000597265 (1:44663995 T>G), RS1000649087 (1:44674584 C>T), RS1000650777 (1:44662566 A>G), RS1000710618 (1:44670694 G>A), RS1000740459 (1:44661393 GCTTT>G), RS1000979304 (1:44657114 G>A), RS1001084314 (1:44657544 C>T), RS1001319461 (1:44669771 T>C), RS1001331585 (1:44676258 C>T)

Disease associations

OMIM: gene MIM:619722 | disease phenotypes: MIM:619727

GenCC curated gene-disease

Disease	Classification	Inheritance
craniotubular dysplasia, Ikegawa type	Strong	Autosomal recessive
skeletal dysplasia	Strong	Autosomal recessive

Mondo (2): craniotubular dysplasia, Ikegawa type (MONDO:0859226), skeletal dysplasia (MONDO:0018230)

Orphanet (0):

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000179	Thick lower lip vermilion
HP:0000215	Thick upper lip vermilion
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000365	Hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000648	Optic atrophy
HP:0000667	Phthisis bulbi
HP:0000771	Gynecomastia
HP:0000885	Broad ribs
HP:0000926	Platyspondyly
HP:0001138	Optic neuropathy
HP:0001263	Global developmental delay
HP:0001629	Ventricular septal defect
HP:0002057	Prominent glabella
HP:0002684	Thickened calvaria
HP:0002694	Sclerosis of skull base
HP:0002753	Thin bony cortex
HP:0003621	Juvenile onset
HP:0004279	Short palm
HP:0004322	Short stature

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, decreases methylation	5
GSK-J4	decreases expression	1
fenofibric acid	affects binding, increases expression	1
butyraldehyde	decreases expression	1
ciglitazone	affects binding, increases expression	1
pentanal	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Niclosamide	increases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Isotretinoin	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001754	Not specified	COMPLETED	Study of Skeletal Disorders and Short Stature
NCT02762318	Not specified	TERMINATED	Identification and Characterization of Bone-related Genetic Variants in Families
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT05247645	Not specified	RECRUITING	Data Collection of Patients With Rare Bone Diseases
NCT05876416	Not specified	RECRUITING	Decoding the Genetic Landscape of Skeletal Diseases
NCT05991609	Not specified	ACTIVE_NOT_RECRUITING	Extreme Morphology and Metabolic Health
NCT06002373	Not specified	UNKNOWN	Assessment of Artificial Intelligence for Treatment Decision Recommendation of Adult Skeletal Class III Patients