BTBD8

Summary

BTBD8 (BTB domain containing 8, HGNC:21019) is a protein-coding gene on chromosome 1p22.1, encoding BTB/POZ domain-containing protein 8 (Q5XKL5). Involved in clathrin-mediated endocytosis at the synapse.

Predicted to be involved in synaptic vesicle budding from endosome and synaptic vesicle endocytosis. Located in nucleoplasm.

Source: NCBI Gene 284697 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 59 total
• MANE Select transcript: NM_001376131

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21019
Approved symbol	BTBD8
Name	BTB domain containing 8
Location	1p22.1
Locus type	gene with protein product
Status	Approved
Aliases	APache
Ensembl gene	ENSG00000189195
Ensembl biotype	protein_coding
OMIM	617945
Entrez	284697

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000342818, ENST00000370382, ENST00000635934, ENST00000636805, ENST00000637221, ENST00000642070, ENST00000674371

RefSeq mRNA: 2 — MANE Select: NM_001376131 NM_001376131, NM_015237

CCDS: CCDS44172, CCDS91000

Canonical transcript exons

ENST00000636805 — 18 exons

Exon	Start	End
ENSE00001818619	92183864	92184723
ENSE00003792846	92166958	92167140
ENSE00003799363	92147684	92147786
ENSE00003815120	92141115	92141211
ENSE00003815358	92168866	92168995
ENSE00003815389	92176829	92177546
ENSE00003815555	92147180	92147268
ENSE00003823007	92088698	92088895
ENSE00003824082	92139350	92139430
ENSE00003824228	92167848	92167985
ENSE00003825243	92171399	92171460
ENSE00003825262	92107884	92108001
ENSE00003826229	92180265	92182595
ENSE00003826551	92178312	92178451
ENSE00003827580	92177811	92177898
ENSE00003828159	92102473	92102669
ENSE00003829105	92129687	92129776
ENSE00003908716	92080345	92080720

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 98.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4174 / max 3803.7078, expressed in 1106 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4026	7.2363	155
4025	3.1576	1071
4027	1.9611	98
4034	0.0625	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	98.17	gold quality
endothelial cell	CL:0000115	96.96	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.81	gold quality
primary visual cortex	UBERON:0002436	95.72	gold quality
middle temporal gyrus	UBERON:0002771	95.38	gold quality
superior frontal gyrus	UBERON:0002661	95.11	gold quality
orbitofrontal cortex	UBERON:0004167	95.01	gold quality
frontal pole	UBERON:0002795	94.72	gold quality
occipital lobe	UBERON:0002021	94.70	gold quality
postcentral gyrus	UBERON:0002581	94.63	gold quality
parietal lobe	UBERON:0001872	94.32	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.56	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.54	gold quality
prefrontal cortex	UBERON:0000451	91.98	gold quality
entorhinal cortex	UBERON:0002728	91.78	gold quality
cerebellar vermis	UBERON:0004720	91.75	gold quality
frontal cortex	UBERON:0001870	91.58	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.93	gold quality
neocortex	UBERON:0001950	90.49	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.37	gold quality
cerebral cortex	UBERON:0000956	89.05	gold quality
right frontal lobe	UBERON:0002810	88.34	gold quality
middle frontal gyrus	UBERON:0002702	87.99	gold quality
telencephalon	UBERON:0001893	87.50	gold quality
cingulate cortex	UBERON:0003027	86.83	gold quality
anterior cingulate cortex	UBERON:0009835	86.77	gold quality
cerebellum	UBERON:0002037	86.49	gold quality
cerebellar cortex	UBERON:0002129	86.07	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.94	gold quality
cerebellar hemisphere	UBERON:0002245	85.92	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	1069.81
E-MTAB-7316	yes	38.21
E-GEOD-137537	yes	15.70
E-GEOD-84465	yes	7.33
E-ANND-3	no	7.29

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• expression pattern of BTBD8 shows it may have a function related to brain development (PMID:14654994)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Btbd8	ENSMUSG00000111375
rattus_norvegicus	Btbd8	ENSRNOG00000023446

Paralogs (1): PRR36 (ENSG00000183248)

Protein

Protein identifiers

BTB/POZ domain-containing protein 8 — Q5XKL5 (reviewed: Q5XKL5)

Alternative names: AP2-interacting clathrin-endocytosis

All UniProt accessions (5): A0A6I8PIJ9, A0A8V8N7F1, A0A8V8SD95, B4DKD6, Q5XKL5

UniProt curated annotations — full annotation on UniProt →

Function. Involved in clathrin-mediated endocytosis at the synapse. Plays a role in neuronal development and in synaptic vesicle recycling in mature neurons, a process required for normal synaptic transmission.

Subunit / interactions. Interacts (via N-terminus) with adapter protein complex AP-2 subunits alpha (AP2A1) and beta (AP2B1).

Subcellular location. Cell projection. Axon. Presynapse. Cytoplasmic vesicle. Clathrin-coated vesicle. Nucleus.

Tissue specificity. Highly expressed in fetal brain. Weakly expressed in adult brain and prostate.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5XKL5-3	3	yes
Q5XKL5-4	4

RefSeq proteins (2): NP_001363060, NP_056052 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR027907	BTBD8_C	Domain
IPR040121	BTBD8_BTB_POZ_1	Domain
IPR043225	BACK_BTBD8	Domain

Pfam: PF00651, PF15363, PF26017

UniProt features (44 total): compositionally biased region 17, sequence variant 13, region of interest 8, domain 2, splice variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5XKL5-F1	47.10	0.15

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 135 (showing top): GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_VESICLE_LOCALIZATION, GOBP_VESICLE_ORGANIZATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_SYNAPTIC_VESICLE_RECYCLING, GOCC_COATED_VESICLE, GOCC_VESICLE_COAT, FREAC4_01, GOCC_NEURON_PROJECTION, GOBP_MEMBRANE_ORGANIZATION, GOBP_IMPORT_INTO_CELL, CHANG_IMMORTALIZED_BY_HPV31_UP, chr1p22, MODULE_95, GOBP_ORGANELLE_LOCALIZATION

GO Biological Process (2): synaptic vesicle budding from endosome (GO:0016182), synaptic vesicle endocytosis (GO:0048488)

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

GO Cellular Component (12): nucleus (GO:0005634), nucleoplasm (GO:0005654), AP-2 adaptor complex (GO:0030122), axon (GO:0030424), neuron projection terminus (GO:0044306), extrinsic component of synaptic vesicle membrane (GO:0098850), synaptic vesicle (GO:0008021), clathrin-coated vesicle (GO:0030136), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202), presynapse (GO:0098793)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
neuron projection	2
synaptic vesicle recycling via endosome	1
intracellular transport	1
synaptic vesicle budding	1
vesicle-mediated transport in synapse	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
clathrin coat of endocytic vesicle	1
clathrin adaptor complex	1
clathrin coat of coated pit	1
plasma membrane protein complex	1
synaptic vesicle membrane	1
extrinsic component of organelle membrane	1
exocytic vesicle	1
presynapse	1
coated vesicle	1
cytoplasm	1
intracellular vesicle	1
cell junction	1
synapse	1

Protein interactions and networks

STRING

1368 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BTBD8	TTLL13	A6NNM8	510
BTBD8	TRAPPC6B	Q86SZ2	507
BTBD8	LRRC40	Q9H9A6	498
BTBD8	PXMP4	Q9Y6I8	485
BTBD8	RNF17	Q9BXT8	476
BTBD8	CATSPER2	Q96P56	476
BTBD8	PTRH2	Q9Y3E5	459
BTBD8	SMIM12	Q96EX1	453
BTBD8	OSTN	P61366	449
BTBD8	C1orf232	A0A0U1RR37	444
BTBD8	SETD5	Q9C0A6	443
BTBD8	CWC15	Q9P013	437
BTBD8	PPP1R3C	Q9UQK1	429
BTBD8	HEMK1	Q9Y5R4	429
BTBD8	ANK2	Q01484	418

IntAct

11 interactions, top by confidence:

A	B	Type	Score
BTBD8	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
BTBD8	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
BTBD8	KIRREL1	psi-mi:“MI:0915”(physical association)	0.400
BTBD8	UBE2D3	psi-mi:“MI:0915”(physical association)	0.370
BTBD8	HSPA8	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
ARHGAP21	CTNND1	psi-mi:“MI:0914”(association)	0.350
WIPI2	VTN	psi-mi:“MI:0914”(association)	0.350
WIPI2	PFKP	psi-mi:“MI:0914”(association)	0.350
SNUPN	BTBD8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): BTBD8 (Affinity Capture-RNA), KIRREL (Affinity Capture-MS), BTBD8 (Affinity Capture-MS), BTBD8 (Affinity Capture-MS), BTBD8 (Protein-peptide), BTBD8 (Affinity Capture-MS), BTBD8 (Affinity Capture-MS), BTBD8 (Affinity Capture-MS), BTBD8 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8HU22, A1A5R8, A8K979, B8A5Y1, E1BB03, F6UH96, O75113, P62283, P62285, P62286, P62287, P62288, P62289, P62290, P62291, P62292, P62293, P62294, P62296, P62297, Q08AX9, Q3MHN7, Q3US16, Q5BKS4, Q5HZL1, Q5XKL5, Q5ZIX8, Q5ZLE9, Q64702, Q68FF0, Q6A037, Q6IE81, Q6NQ79, Q6NSI8, Q6NZP1, Q6PCM1, Q8BMI4, Q8BVE8, Q8BZ05, Q8CJ27

Diamond homologs: A4IFG2, A9JRD8, B1WBS3, B2RXF5, D3YUB6, D4A0X3, O88939, O93567, O95365, P0DMR5, P97302, P97303, Q08BL9, Q0P4X6, Q24174, Q2LE78, Q2M2N2, Q52KB5, Q56A24, Q5PQR3, Q5TZE1, Q5XKL5, Q6GR09, Q6IQ16, Q6NYM1, Q6TFL4, Q717B2, Q717B4, Q7T330, Q811H0, Q8BRG6, Q8C726, Q8CFE5, Q8CII0, Q8K2J9, Q8NAP8, Q8NCP5, Q8R0A2, Q96Q07, Q9BYV9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2539 predictions. Top by Δscore:

Variant	Effect	Δscore
1:92088693:TATA:T	acceptor_loss	1.0000
1:92088695:TA:T	acceptor_loss	1.0000
1:92088696:A:AG	acceptor_gain	1.0000
1:92088696:A:C	acceptor_loss	1.0000
1:92088697:G:GG	acceptor_gain	1.0000
1:92088894:CA:C	donor_gain	1.0000
1:92088894:CAG:C	donor_loss	1.0000
1:92088896:G:GG	donor_gain	1.0000
1:92088897:TAAGT:T	donor_loss	1.0000
1:92102468:TTTA:T	acceptor_loss	1.0000
1:92102470:TA:T	acceptor_loss	1.0000
1:92102471:A:AG	acceptor_gain	1.0000
1:92102471:AG:A	acceptor_gain	1.0000
1:92102472:G:GA	acceptor_gain	1.0000
1:92102472:GG:G	acceptor_gain	1.0000
1:92102472:GGATT:G	acceptor_gain	1.0000
1:92102668:TGGTG:T	donor_loss	1.0000
1:92102670:GTGAG:G	donor_loss	1.0000
1:92102671:T:A	donor_loss	1.0000
1:92107881:A:G	acceptor_gain	1.0000
1:92129775:GG:G	donor_gain	1.0000
1:92129776:GG:G	donor_gain	1.0000
1:92139348:A:AG	acceptor_gain	1.0000
1:92139349:G:GA	acceptor_gain	1.0000
1:92139349:GT:G	acceptor_gain	1.0000
1:92139349:GTAT:G	acceptor_gain	1.0000
1:92139349:GTATA:G	acceptor_gain	1.0000
1:92139426:GTTGG:G	donor_gain	1.0000
1:92141113:A:AG	acceptor_gain	1.0000
1:92141114:G:GG	acceptor_gain	1.0000

AlphaMissense

11942 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:92181584:A:C	S788R	0.998
1:92181586:C:A	S788R	0.998
1:92181586:C:G	S788R	0.998
1:92181587:A:C	S789R	0.998
1:92181589:T:A	S789R	0.998
1:92181589:T:G	S789R	0.998
1:92181596:A:C	S792R	0.998
1:92181598:T:A	S792R	0.998
1:92181598:T:G	S792R	0.998
1:92181612:T:C	L797S	0.998
1:92181581:A:C	S787R	0.997
1:92181583:T:A	S787R	0.997
1:92181583:T:G	S787R	0.997
1:92184298:T:A	W1270R	0.997
1:92184298:T:C	W1270R	0.997
1:92184134:T:C	L1215P	0.996
1:92184314:T:C	L1275P	0.996
1:92181569:T:C	F783L	0.995
1:92181571:T:A	F783L	0.995
1:92181571:T:G	F783L	0.995
1:92184053:T:C	L1188P	0.994
1:92184062:T:C	L1191P	0.994
1:92181485:G:C	D755H	0.993
1:92181472:G:C	K750N	0.992
1:92181472:G:T	K750N	0.992
1:92181590:G:C	D790H	0.992
1:92181932:T:C	F904L	0.992
1:92181934:T:A	F904L	0.992
1:92181934:T:G	F904L	0.992
1:92181999:T:C	L926S	0.992

dbSNP variants (sampled 300 via entrez): RS1000003590 (1:92115411 C>T), RS1000026652 (1:92163020 A>G), RS1000077487 (1:92111286 C>T), RS1000107524 (1:92152164 G>C), RS1000146456 (1:92156211 G>T), RS1000185502 (1:92108989 G>A,T), RS1000199069 (1:92156301 G>A), RS1000209987 (1:92163199 C>CA), RS1000235788 (1:92124876 A>G), RS1000236366 (1:92169589 A>C), RS1000265927 (1:92108819 T>A), RS1000305082 (1:92118288 T>C), RS1000329121 (1:92085663 G>A,C), RS1000374129 (1:92131247 A>C), RS1000389803 (1:92176070 A>G)

Disease associations

OMIM: gene MIM:617945 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001762_127	Obesity-related traits	2.000000e-06
GCST003043_175	Inflammatory bowel disease	1.000000e-08
GCST003044_4	Crohn’s disease	2.000000e-06
GCST003622_22	Systemic lupus erythematosus	6.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	5
trichostatin A	affects cotreatment, decreases expression	3
methylmercuric chloride	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Catechin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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