KCTD8

Summary

KCTD8 (potassium channel tetramerization domain containing 8, HGNC:22394) is a protein-coding gene on chromosome 4p13, encoding BTB/POZ domain-containing protein KCTD8 (Q6ZWB6). Auxiliary subunit of GABA-B receptors that determine the pharmacology and kinetics of the receptor response.

Predicted to enable G protein-coupled neurotransmitter receptor activity involved in regulation of presynaptic membrane potential. Predicted to be involved in regulation of G protein-coupled receptor signaling pathway. Predicted to be located in cell projection and postsynaptic membrane. Predicted to be part of receptor complex. Predicted to be active in postsynapse and presynaptic active zone membrane.

Source: NCBI Gene 386617 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 90 total
• Druggable target: yes
• MANE Select transcript: NM_198353

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22394
Approved symbol	KCTD8
Name	potassium channel tetramerization domain containing 8
Location	4p13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000183783
Ensembl biotype	protein_coding
OMIM	618442
Entrez	386617

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000360029, ENST00000515268, ENST00000903710, ENST00000954398

RefSeq mRNA: 1 — MANE Select: NM_198353 NM_198353

CCDS: CCDS3467

Canonical transcript exons

ENST00000360029 — 2 exons

Exon	Start	End
ENSE00001400795	44447563	44448809
ENSE00001489386	44173903	44175250

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 99.26.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7151 / max 86.0297, expressed in 405 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51982	1.2011	325
51984	0.2463	121
51981	0.1563	88
51983	0.1114	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	99.26	gold quality
corpus callosum	UBERON:0002336	88.43	gold quality
cerebellum	UBERON:0002037	85.06	gold quality
cerebellar cortex	UBERON:0002129	85.03	gold quality
cerebellar hemisphere	UBERON:0002245	84.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.17	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.69	gold quality
prefrontal cortex	UBERON:0000451	81.65	gold quality
superior frontal gyrus	UBERON:0002661	81.10	gold quality
primary visual cortex	UBERON:0002436	80.65	gold quality
spinal cord	UBERON:0002240	79.59	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	79.57	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.40	gold quality
nucleus accumbens	UBERON:0001882	79.38	gold quality
frontal cortex	UBERON:0001870	78.89	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.13	gold quality
cerebral cortex	UBERON:0000956	76.89	gold quality
caudate nucleus	UBERON:0001873	76.30	gold quality
putamen	UBERON:0001874	75.79	gold quality
anterior cingulate cortex	UBERON:0009835	74.96	gold quality
right frontal lobe	UBERON:0002810	74.63	gold quality
brain	UBERON:0000955	73.80	gold quality
hypothalamus	UBERON:0001898	73.76	gold quality
substantia nigra	UBERON:0002038	73.52	gold quality
temporal lobe	UBERON:0001871	72.97	gold quality
amygdala	UBERON:0001876	72.86	gold quality
Ammon’s horn	UBERON:0001954	72.63	gold quality
islet of Langerhans	UBERON:0000006	71.73	gold quality
quadriceps femoris	UBERON:0001377	70.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting KCTD8, 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-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-513A-5P	100.00	69.77	2465
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
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-3910	99.95	71.13	2227
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-9983-3P	99.94	71.48	3631

Literature-anchored findings (GeneRIF, showing 3)

• KCTD8 might modulate adverse effects of smoking during pregnancy on brain development via apoptosis triggered by low intracellular levels of potassium, possibly reducing the number of progenitor cells (PMID:22156575)
• Data indicate that median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were >/=30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. (PMID:22930747)
• Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling. (PMID:39023358)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kctd8	ENSDARG00000067507
mus_musculus	Kctd8	ENSMUSG00000037653
rattus_norvegicus	Kctd8	ENSRNOG00000063710
drosophila_melanogaster	twz	FBGN0034636
caenorhabditis_elegans	F32B4.5	WBGENE00009315

Paralogs (13): KCTD1 (ENSG00000134504), KCTD14 (ENSG00000151364), KCTD15 (ENSG00000153885), KCTD18 (ENSG00000155729), KCTD6 (ENSG00000168301), KCTD19 (ENSG00000168676), KCTD12 (ENSG00000178695), KCTD4 (ENSG00000180332), KCTD16 (ENSG00000183775), KCTD21 (ENSG00000188997), KCNRG (ENSG00000198553), KCTD11 (ENSG00000213859), KCTD7 (ENSG00000243335)

Protein

Protein identifiers

BTB/POZ domain-containing protein KCTD8 — Q6ZWB6 (reviewed: Q6ZWB6)

All UniProt accessions (2): Q6ZWB6, H0Y9S2

UniProt curated annotations — full annotation on UniProt →

Function. Auxiliary subunit of GABA-B receptors that determine the pharmacology and kinetics of the receptor response. Increases agonist potency and markedly alter the G-protein signaling of the receptors by accelerating onset and promoting desensitization.

Subunit / interactions. Interacts as a tetramer with GABRB1 and GABRB2.

Subcellular location. Presynaptic cell membrane. Postsynaptic cell membrane.

RefSeq proteins (1): NP_938167* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR003131	T1-type_BTB	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR049904	H1_KCTD8	Domain
IPR057093	H1_KCTD8_12_16	Domain

Pfam: PF02214, PF23110

UniProt features (19 total): strand 5, helix 3, compositionally biased region 3, modified residue 3, region of interest 2, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6G57	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZWB6-F1	67.75	0.33

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 78, 80, 410

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 111 (showing top): ATF_B, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, CREBP1_Q2, CAGCTG_AP4_Q5, ATGTTAA_MIR302C, ATF1_Q6, TGIF_01, CREB_Q2_01, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, GOBP_PROTEIN_HOMOOLIGOMERIZATION, CREBP1CJUN_01, GOCC_POSTSYNAPSE, CREB_01, GOCC_SYNAPSE, GOCC_POSTSYNAPTIC_MEMBRANE

GO Biological Process (2): regulation of G protein-coupled receptor signaling pathway (GO:0008277), protein homooligomerization (GO:0051260)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (9): signaling receptor complex (GO:0043235), postsynaptic membrane (GO:0045211), presynaptic active zone membrane (GO:0048787), plasma membrane (GO:0005886), membrane (GO:0016020), presynaptic membrane (GO:0042734), cell projection (GO:0042995), synapse (GO:0045202), postsynapse (GO:0098794)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synaptic membrane	3
cellular anatomical structure	3
G protein-coupled receptor signaling pathway	1
regulation of signal transduction	1
protein complex oligomerization	1
protein binding	1
binding	1
protein-containing complex	1
postsynapse	1
presynaptic membrane	1
presynaptic active zone	1
membrane	1
cell periphery	1
presynapse	1
cell junction	1
synapse	1

Protein interactions and networks

STRING

930 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCTD8	KCTD11	Q693B1	680
KCTD8	CUL3	Q13618	599
KCTD8	KCTD20	Q7Z5Y7	539
KCTD8	KCTD19	Q17RG1	533
KCTD8	GABBR1	Q9UBS5	523
KCTD8	BTBD10	Q9BSF8	482
KCTD8	SSTR3	P32745	451
KCTD8	COX7B2	Q8TF08	418
KCTD8	KCTD16	Q68DU8	410
KCTD8	KCTD12	Q96CX2	401
KCTD8	RPS26	P02383	395
KCTD8	YIPF7	Q8N8F6	389
KCTD8	ESRRG	P62508	389
KCTD8	GABRG1	Q8N1C3	367
KCTD8	LRRC66	Q68CR7	366

IntAct

20 interactions, top by confidence:

A	B	Type	Score
HNRNPK	KCTD8	psi-mi:“MI:0915”(physical association)	0.560
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
CEP162	KCTD8	psi-mi:“MI:0915”(physical association)	0.400
KCTD8	YWHAE	psi-mi:“MI:0915”(physical association)	0.400
SFN	KCTD8	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	KCTD8	psi-mi:“MI:0915”(physical association)	0.400
EGFR	KCTD8	psi-mi:“MI:0915”(physical association)	0.370
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
RIMS1	PSMD12	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
FAM110B		psi-mi:“MI:0914”(association)	0.350
KCTD12	CYTH3	psi-mi:“MI:0914”(association)	0.350
SOHLH1	KCTD8	psi-mi:“MI:0914”(association)	0.350
HNRNPK	KCTD8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): KCTD8 (Affinity Capture-MS), KCTD8 (Two-hybrid), KCTD8 (Affinity Capture-MS), KCTD8 (Cross-Linking-MS (XL-MS)), KCTD8 (Affinity Capture-Western), KCTD5 (FRET), KCTD5 (Affinity Capture-Luminescence), KCTD8 (Affinity Capture-MS), KCTD8 (Affinity Capture-Luminescence)

ESM2 similar proteins: A0A088MLT8, A2AQ25, B3KU38, B5DF41, E9PSK7, O15079, O35274, P0DPB3, P0DPB4, P12755, P49140, P85299, Q0D2I5, Q14DQ1, Q1LY51, Q3B7M3, Q3SYW5, Q4KMA0, Q4R3X1, Q50H33, Q5F3L9, Q5FVG6, Q5RD40, Q5XKK7, Q60698, Q6ZNC4, Q6ZUS6, Q6ZWB6, Q80U23, Q80U62, Q80XA6, Q812A5, Q86YI8, Q8BXL9, Q8K2W6, Q8ND83, Q8NFH8, Q8QFX1, Q8TEK3, Q924W7

Diamond homologs: A3KMV1, A4IFB4, A5PKG7, A6H6X4, B1WC97, B5DEL1, D5SHR0, G5EFC3, O65555, P0C5J9, P15388, P17971, P17972, P25122, P48547, P59994, P59995, Q01956, Q03607, Q03719, Q0VD00, Q0VFV7, Q14003, Q14681, Q29RJ0, Q2HJ48, Q2TUM3, Q3URF8, Q4G0X4, Q50H33, Q52PG9, Q54KH0, Q5DTY9, Q5M956, Q5XJ34, Q5ZJP7, Q62897, Q63881, Q63959, Q68DU8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	83
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2203 predictions. Top by Δscore:

Variant	Effect	Δscore
4:44175246:TGGTC:T	acceptor_gain	1.0000
4:44175247:GGTC:G	acceptor_gain	1.0000
4:44175248:GTC:G	acceptor_gain	1.0000
4:44175249:TC:T	acceptor_gain	1.0000
4:44175250:CC:C	acceptor_gain	1.0000
4:44175251:C:CC	acceptor_gain	1.0000
4:44175251:C:CG	acceptor_loss	1.0000
4:44276040:T:TA	donor_gain	1.0000
4:44276041:C:A	donor_gain	1.0000
4:44293797:A:AC	donor_gain	1.0000
4:44293798:C:CC	donor_gain	1.0000
4:44299066:A:AC	donor_gain	1.0000
4:44299067:C:CC	donor_gain	1.0000
4:44447561:A:AC	donor_gain	1.0000
4:44447562:C:CC	donor_gain	1.0000
4:44447562:CGGA:C	donor_gain	1.0000
4:44259246:CACA:C	acceptor_gain	0.9900
4:44259249:A:C	acceptor_gain	0.9900
4:44275979:A:C	donor_gain	0.9900
4:44276002:A:AC	donor_gain	0.9900
4:44376760:A:AC	donor_gain	0.9900
4:44447558:CTT:C	donor_loss	0.9900
4:44447561:ACGGA:A	donor_loss	0.9900
4:44447562:C:CG	donor_loss	0.9900
4:44447562:CG:C	donor_gain	0.9900
4:44447562:CGG:C	donor_gain	0.9900
4:44447562:CGGAA:C	donor_gain	0.9900
4:44175248:GTCCT:G	acceptor_gain	0.9800
4:44175251:C:T	acceptor_gain	0.9800
4:44276003:T:C	donor_gain	0.9800

AlphaMissense

3100 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:44174823:C:A	W463C	1.000
4:44174823:C:G	W463C	1.000
4:44174825:A:G	W463R	1.000
4:44174825:A:T	W463R	1.000
4:44447661:A:G	F288S	1.000
4:44447676:A:G	L283P	1.000
4:44447712:A:G	L271P	1.000
4:44447712:A:T	L271H	1.000
4:44447716:A:C	Y270D	1.000
4:44447769:A:G	L252P	1.000
4:44447769:A:T	L252H	1.000
4:44447808:C:T	G239E	1.000
4:44447809:C:A	G239W	1.000
4:44447809:C:G	G239R	1.000
4:44447809:C:T	G239R	1.000
4:44448108:A:G	L139P	1.000
4:44448114:A:G	F137S	1.000
4:44448123:G:T	A134D	1.000
4:44448124:C:G	A134P	1.000
4:44448135:A:G	L130P	1.000
4:44448135:A:T	L130Q	1.000
4:44448152:G:C	F124L	1.000
4:44448152:G:T	F124L	1.000
4:44448153:A:C	F124C	1.000
4:44448153:A:G	F124S	1.000
4:44448154:A:G	F124L	1.000
4:44448183:C:G	R114P	1.000
4:44448184:G:A	R114W	1.000
4:44448186:A:G	L113P	1.000
4:44448192:T:A	D111V	1.000

dbSNP variants (sampled 300 via entrez): RS1000000461 (4:44429724 T>C), RS1000011987 (4:44208178 C>A), RS1000022713 (4:44291035 A>C,G), RS1000037141 (4:44311375 T>C), RS1000043265 (4:44444809 A>C,G), RS1000045529 (4:44300544 C>A,T), RS1000047923 (4:44216521 G>C), RS1000052356 (4:44387131 C>T), RS1000064208 (4:44208527 T>C), RS1000099200 (4:44258931 C>T), RS1000099605 (4:44224072 A>C), RS1000102191 (4:44270946 C>T), RS1000103150 (4:44310226 C>G), RS1000110192 (4:44311136 T>TAA), RS1000112650 (4:44339405 T>A)

Disease associations

OMIM: gene MIM:618442 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001365_3	Anticoagulant levels	3.000000e-06
GCST001651_84	Response to amphetamines	9.000000e-06
GCST002817_2	Alzheimer’s disease in APOE e4- carriers	3.000000e-06
GCST006462_10	Uterine fibroids	4.000000e-10
GCST010989_240	Body size at age 10	2.000000e-08
GCST011742_27	Triglyceride levels in HIV infection	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004637	protein S measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523356 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
methylmercuric chloride	increases expression	1
bisphenol A	increases methylation	1
arsenite	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Diazinon	decreases methylation	1
Lead	affects expression	1
Silicon Dioxide	increases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4322701	Binding	Displacement of TAMRA-AAG-SLQLPILHHAYLPSIGGV from recombinant human 6X His-tagged KCTD8 T1 domain (37 to 148 residues) expressed in Escherichia coli BL21 DE3 cells by fluorescence polarization assay	Targeting the γ-Aminobutyric Acid Type B (GABAB) Receptor Complex: Development of Inhibitors Targeting the K+ Channel Tetramerization Domain (KCTD) Containing Proteins/GABAB Receptor Protein-Protein Interaction. — J Med Chem

Clinical trials (associated diseases)

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