TMEM35A

Summary

TMEM35A (transmembrane protein 35A, HGNC:25864) is a protein-coding gene on chromosome Xq22.1, encoding Novel acetylcholine receptor chaperone (Q53FP2). Molecular chaperone which mediates the proper assembly and functional expression of the nicotinic acetylcholine receptors (nAChRs) throughout the brain.

Enables acetylcholine receptor regulator activity. Involved in chaperone-mediated protein complex assembly and positive regulation of protein localization to cell surface. Located in endoplasmic reticulum.

Source: NCBI Gene 59353 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 7 total
• MANE Select transcript: NM_021637

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25864
Approved symbol	TMEM35A
Name	transmembrane protein 35A
Location	Xq22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14084, TUF-1, NACHO
Ensembl gene	ENSG00000126950
Ensembl biotype	protein_coding
Entrez	59353

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000372930, ENST00000478351

RefSeq mRNA: 1 — MANE Select: NM_021637 NM_021637

CCDS: CCDS14478

Canonical transcript exons

ENST00000372930 — 2 exons

Exon	Start	End
ENSE00000868918	101094573	101096367
ENSE00001854412	101078879	101079122

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 98.37.

FANTOM5 (CAGE): breadth broad, TPM avg 8.6749 / max 218.4504, expressed in 835 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196940	8.6749	835

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.37	gold quality
ganglionic eminence	UBERON:0004023	96.76	gold quality
superior vestibular nucleus	UBERON:0007227	93.42	gold quality
pons	UBERON:0000988	92.83	gold quality
hypothalamus	UBERON:0001898	92.83	gold quality
prefrontal cortex	UBERON:0000451	92.08	gold quality
nucleus accumbens	UBERON:0001882	91.58	gold quality
cerebellar vermis	UBERON:0004720	91.48	gold quality
substantia nigra pars compacta	UBERON:0001965	91.39	gold quality
seminal vesicle	UBERON:0000998	91.20	gold quality
cerebellar cortex	UBERON:0002129	91.12	gold quality
cerebellar hemisphere	UBERON:0002245	91.06	gold quality
cerebellum	UBERON:0002037	91.03	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.82	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.69	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.19	gold quality
frontal cortex	UBERON:0001870	90.05	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.04	gold quality
neocortex	UBERON:0001950	89.89	gold quality
anterior cingulate cortex	UBERON:0009835	89.52	gold quality
cingulate cortex	UBERON:0003027	89.45	gold quality
cerebral cortex	UBERON:0000956	89.42	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.11	gold quality
dorsal root ganglion	UBERON:0000044	89.07	gold quality
saphenous vein	UBERON:0007318	88.36	gold quality
telencephalon	UBERON:0001893	88.32	gold quality
right frontal lobe	UBERON:0002810	88.31	gold quality
amygdala	UBERON:0001876	88.18	gold quality
substantia nigra pars reticulata	UBERON:0001966	88.00	gold quality
postcentral gyrus	UBERON:0002581	87.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	15.60
E-ANND-3	no	3.18

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

98 targeting TMEM35A, 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-8485	100.00	77.57	4731
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-188-3P	100.00	68.76	1240
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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-570-3P	99.96	72.41	4910
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-1250-3P	99.96	70.04	4038
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-652-5P	99.91	67.49	505

Literature-anchored findings (GeneRIF, showing 2)

• NACHO and 14-3-3 promote expression of distinct subunit stoichiometries of the alpha4beta2 acetylcholine receptor. (PMID:32676916)
• Unbalanced Regulation of alpha7 nAChRs by Ly6h and NACHO Contributes to Neurotoxicity in Alzheimer’s Disease. (PMID:34446574)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem35	ENSDARG00000052567
mus_musculus	Tmem35a	ENSMUSG00000033578
rattus_norvegicus	Tmem35a	ENSRNOG00000001506
drosophila_melanogaster	CG13920	FBGN0025712

Paralogs (1): TMEM35B (ENSG00000243749)

Protein

Protein identifiers

Novel acetylcholine receptor chaperone — Q53FP2 (reviewed: Q53FP2)

All UniProt accessions (1): Q53FP2

UniProt curated annotations — full annotation on UniProt →

Function. Molecular chaperone which mediates the proper assembly and functional expression of the nicotinic acetylcholine receptors (nAChRs) throughout the brain. Essential for the proper folding, assembly, function and surface trafficking of alpha-7 (CHRNA7), alpha-4-beta-2, alpha-3-beta-2 and alpha-3-beta-4 receptors. Stably associates with ribophorin-1 (RPN1) and ribophorin-2 (RPN2) (components of the oligosaccharyl transferase (OST) complex) and with calnexin (CANX), both of which are critical for NACHO-mediated effects on CHRNA7 assembly and function. Facilitates the proper folding and assembly of alpha-6-beta-2 and alpha-6-beta-2-beta-3 receptors and acts at early stages of the nAChRs subunit assembly. Promotes the expression of the alpha-4(2):beta-2(3) stoichiometric form over the alpha-4(3):beta-2(2) form.

Subunit / interactions. May interact with NGFR. Interacts with RPN1, RPN2 and CANX.

Subcellular location. Peroxisome membrane. Cytoplasmic vesicle. Endoplasmic reticulum membrane.

Similarity. Belongs to the DoxX family.

RefSeq proteins (1): NP_067650* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR040399	TMEM35A/B	Family

UniProt features (14 total): topological domain 5, transmembrane region 4, region of interest 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9H9E	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53FP2-F1	81.54	0.61

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 136 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GNF2_RTN1, RRAGTTGT_UNKNOWN, WALLACE_PROSTATE_CANCER_RACE_UP, RORA1_01, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_SURFACE, TGACCTY_ERR1_Q2, GOBP_CHAPERONE_MEDIATED_PROTEIN_COMPLEX_ASSEMBLY, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_SURFACE, NF1_Q6_01, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, ATTCTTT_MIR186, MYOD_Q6

GO Biological Process (2): chaperone-mediated protein complex assembly (GO:0051131), positive regulation of protein localization to cell surface (GO:2000010)

GO Molecular Function (2): acetylcholine receptor regulator activity (GO:0030548), protein binding (GO:0005515)

GO Cellular Component (6): peroxisomal membrane (GO:0005778), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytoplasmic vesicle (GO:0031410), peroxisome (GO:0005777), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
protein-containing complex assembly	1
protein localization to cell surface	1
positive regulation of protein localization	1
regulation of protein localization to cell surface	1
acetylcholine receptor activity	1
neurotransmitter receptor regulator activity	1
binding	1
peroxisome	1
microbody membrane	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular vesicle	1
microbody	1
cellular anatomical structure	1

Protein interactions and networks

STRING

582 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM35A	RIC3	Q7Z5B4	571
TMEM35A	TMEM35B	Q8NCS4	480
TMEM35A	ARHGAP39	Q9C0H5	474
TMEM35A	SIPA1L1	O43166	459
TMEM35A	GALM	Q96C23	441
TMEM35A	GOLGB1	Q14789	408
TMEM35A	TMEM217	Q8N7C4	383
TMEM35A	TMEM217B	A0A494BZU4	380
TMEM35A	CLYBL	Q8N0X4	370
TMEM35A	FAM110D	Q8TAY7	370
TMEM35A	KIAA1210	Q9ULL0	370
TMEM35A	EXOC1	Q9NV70	360
TMEM35A	ANKRD34A	Q69YU3	351
TMEM35A	NFASC	O94856	345
TMEM35A	ZFP14	Q9HCL3	340

IntAct

97 interactions, top by confidence:

A	B	Type	Score
TMEM35A	TMEM106C	psi-mi:“MI:0915”(physical association)	0.560
VAMP3	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	TMEM120A	psi-mi:“MI:0915”(physical association)	0.560
BET1	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	FXYD6	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	TMEM201	psi-mi:“MI:0915”(physical association)	0.560
CYB5B	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	RTP2	psi-mi:“MI:0915”(physical association)	0.560
THBD	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
EHHADH	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
MGLL	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	GIMAP1	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	TMEM42	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	TMEM243	psi-mi:“MI:0915”(physical association)	0.560
GOSR2	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
ADIPOQ	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	COX20	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	TMEM229B	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	FIMP	psi-mi:“MI:0915”(physical association)	0.560
CXCL16	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	VAPA	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	LNPEP	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	PPGB	psi-mi:“MI:0915”(physical association)	0.560
VAMP1	TMEM35A	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	RUSF1	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A		psi-mi:“MI:0915”(physical association)	0.560

BioGRID (37): TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), TMEM35 (Two-hybrid), ORMDL1 (Two-hybrid), TMEM106C (Two-hybrid), TMEM243 (Two-hybrid), FXYD6 (Two-hybrid), VAMP1 (Two-hybrid)

ESM2 similar proteins: A2AWR3, A4IGI5, D3ZYP5, O18405, O88496, P38435, P52650, P58355, Q07175, Q0P4Y8, Q18864, Q28FA9, Q3KQE5, Q3KTM2, Q3U0Y2, Q4R5F4, Q4V3B8, Q4V8K1, Q53FP2, Q53P98, Q58EL2, Q5E9T5, Q5R9A7, Q5RCJ4, Q5RF50, Q68FV1, Q6GN30, Q6JAM9, Q6P2T0, Q6P8F8, Q6ZPD9, Q6ZQE4, Q71B07, Q7Z3F1, Q7ZVP8, Q7ZWN0, Q7ZY07, Q8NCS4, Q923B6, Q95L73

Diamond homologs: A4IGI5, Q4R5F4, Q53FP2, Q58EL2, Q5E9T5, Q6JAM9, Q9D328

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

296 predictions. Top by Δscore:

Variant	Effect	Δscore
X:101094571:A:AG	acceptor_gain	1.0000
X:101094572:G:GG	acceptor_gain	1.0000
X:101094572:GAAAC:G	acceptor_gain	1.0000
X:101079119:GATG:G	donor_gain	0.9900
X:101079121:TGG:T	donor_loss	0.9900
X:101079123:G:GG	donor_gain	0.9900
X:101079123:GTA:G	donor_loss	0.9900
X:101079124:T:TC	donor_loss	0.9900
X:101094557:A:AG	acceptor_gain	0.9900
X:101094558:A:G	acceptor_gain	0.9900
X:101094566:A:AG	acceptor_gain	0.9900
X:101094567:C:G	acceptor_gain	0.9900
X:101094570:TA:T	acceptor_loss	0.9900
X:101094571:AG:A	acceptor_loss	0.9900
X:101094572:GA:G	acceptor_gain	0.9900
X:101094572:GAA:G	acceptor_gain	0.9900
X:101094572:GAAA:G	acceptor_gain	0.9900
X:101079121:TG:T	donor_gain	0.9800
X:101079122:GG:G	donor_gain	0.9800
X:101094560:A:AG	acceptor_gain	0.9800
X:101094561:T:G	acceptor_gain	0.9800
X:101079125:AAGT:A	donor_loss	0.9700
X:101079118:AGATG:A	donor_gain	0.9400
X:101079119:GATGG:G	donor_gain	0.9400
X:101079120:ATG:A	donor_gain	0.9400
X:101081820:T:A	acceptor_gain	0.9400
X:101086217:TTC:T	donor_gain	0.9200
X:101079105:G:GT	donor_gain	0.9000
X:101080157:TC:T	donor_gain	0.9000
X:101094570:TAGAA:T	acceptor_gain	0.8900

AlphaMissense

1062 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:101079037:T:A	L12H	1.000
X:101079051:G:A	G17R	1.000
X:101079051:G:C	G17R	1.000
X:101079052:G:A	G17E	1.000
X:101079060:T:C	F20L	1.000
X:101079062:T:A	F20L	1.000
X:101079062:T:G	F20L	1.000
X:101079072:G:A	G24R	1.000
X:101079072:G:C	G24R	1.000
X:101079072:G:T	G24W	1.000
X:101079073:G:A	G24E	1.000
X:101079073:G:T	G24V	1.000
X:101079083:G:C	K27N	1.000
X:101079083:G:T	K27N	1.000
X:101079085:T:C	L28P	1.000
X:101094657:G:C	G69R	1.000
X:101094657:G:T	G69C	1.000
X:101094658:G:A	G69D	1.000
X:101094658:G:T	G69V	1.000
X:101094678:G:C	G76R	1.000
X:101094678:G:T	G76C	1.000
X:101094679:G:A	G76D	1.000
X:101094679:G:T	G76V	1.000
X:101094721:C:A	A90D	1.000
X:101094725:C:A	N91K	1.000
X:101094725:C:G	N91K	1.000
X:101094733:T:C	L94P	1.000
X:101094765:C:G	H105D	1.000
X:101094816:G:A	G122R	1.000
X:101094816:G:C	G122R	1.000

dbSNP variants (sampled 300 via entrez): RS1000155550 (X:101084827 T>C), RS1000166460 (X:101092722 C>CA), RS1000173609 (X:101093915 G>A,T), RS1000209796 (X:101085339 G>A,C), RS1000382303 (X:101085700 G>A,C,T), RS1000507839 (X:101095795 G>T), RS1000754831 (X:101086045 C>T), RS1000776328 (X:101078560 G>A), RS1001122520 (X:101087642 A>G), RS1001667352 (X:101093822 G>A), RS1001727177 (X:101085555 C>T), RS1001938933 (X:101095111 A>G), RS1001969964 (X:101095326 C>T), RS1002151783 (X:101084721 T>G), RS1002160295 (X:101083158 T>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

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

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
testosterone undecanoate	affects cotreatment, decreases expression	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 expression	1
Sunitinib	decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ivermectin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Tunicamycin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Aflatoxin B1	decreases methylation	1
Levonorgestrel	affects cotreatment, decreases expression	1
Antirheumatic Agents	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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