KCTD6

Summary

KCTD6 (potassium channel tetramerization domain containing 6, HGNC:22235) is a protein-coding gene on chromosome 3p14.3, encoding BTB/POZ domain-containing protein KCTD6 (Q8NC69). Probable substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex mediating the ubiquitination and subsequent proteasomal degradation of target proteins.

Enables ankyrin binding activity; cullin family protein binding activity; and identical protein binding activity. Involved in negative regulation of smoothened signaling pathway and ubiquitin-dependent protein catabolic process. Predicted to be located in cytosol.

Source: NCBI Gene 200845 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 13 total
• MANE Select transcript: NM_001128214

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22235
Approved symbol	KCTD6
Name	potassium channel tetramerization domain containing 6
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC27385, KCASH3
Ensembl gene	ENSG00000168301
Ensembl biotype	protein_coding
OMIM	618791
Entrez	200845

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000355076, ENST00000404589, ENST00000479179, ENST00000479470, ENST00000490264, ENST00000491093, ENST00000863654, ENST00000863658, ENST00000863659, ENST00000863660, ENST00000931986, ENST00000961579, ENST00000961580, ENST00000961581

RefSeq mRNA: 2 — MANE Select: NM_001128214 NM_001128214, NM_153331

CCDS: CCDS2891

Canonical transcript exons

ENST00000404589 — 3 exons

Exon	Start	End
ENSE00001561036	58492096	58492169
ENSE00001868563	58500946	58502356
ENSE00003524097	58498713	58498782

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 96.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.4820 / max 32.4536, expressed in 1573 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37051	4.2411	1547
37050	0.2408	98

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	96.10	gold quality
cerebellar vermis	UBERON:0004720	96.08	gold quality
buccal mucosa cell	CL:0002336	95.98	gold quality
oviduct epithelium	UBERON:0004804	95.70	gold quality
cerebellar hemisphere	UBERON:0002245	94.51	gold quality
endothelial cell	CL:0000115	94.50	gold quality
cerebellum	UBERON:0002037	94.49	gold quality
cerebellar cortex	UBERON:0002129	94.47	gold quality
ganglionic eminence	UBERON:0004023	94.46	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.42	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.77	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.73	gold quality
corpus epididymis	UBERON:0004359	93.68	gold quality
kidney epithelium	UBERON:0004819	93.64	gold quality
germinal epithelium of ovary	UBERON:0001304	93.53	gold quality
substantia nigra pars compacta	UBERON:0001965	93.37	gold quality
caput epididymis	UBERON:0004358	93.02	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.01	gold quality
ventricular zone	UBERON:0003053	92.98	gold quality
middle temporal gyrus	UBERON:0002771	92.51	gold quality
entorhinal cortex	UBERON:0002728	91.41	gold quality
lower esophagus mucosa	UBERON:0035834	91.09	gold quality
pons	UBERON:0000988	91.05	gold quality
postcentral gyrus	UBERON:0002581	90.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.51	gold quality
parietal lobe	UBERON:0001872	90.40	gold quality
Ammon’s horn	UBERON:0001954	90.39	gold quality
occipital lobe	UBERON:0002021	90.31	gold quality
superior frontal gyrus	UBERON:0002661	90.27	gold quality
primary visual cortex	UBERON:0002436	90.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting KCTD6, 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-6798-5P	100.00	65.77	699
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-1911-3P	99.15	66.17	528
HSA-MIR-140-3P	99.04	67.69	1324

Literature-anchored findings (GeneRIF, showing 3)

• Rescuing KCASHs expression reduces the Hedgehog-dependent medulloblastoma growth, suggesting that loss of members of this novel family of native HDAC inhibitors is crucial in sustaining Hh pathway-mediated tumorigenesis. (PMID:21472142)
• Obscurin and KCTD6 regulate cullin-dependent small ankyrin-1 (sAnk1.5) protein turnover (PMID:22573887)
• A biophysical characterization of the POZ/BTB of KCTD6, is reported. (PMID:24307990)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	kctd6b	ENSDARG00000023703
danio_rerio	kctd6a	ENSDARG00000043095
mus_musculus	Kctd6	ENSMUSG00000021752
rattus_norvegicus	Kctd6	ENSRNOG00000007817
drosophila_melanogaster	twz	FBGN0034636
caenorhabditis_elegans	F32B4.5	WBGENE00009315

Paralogs (13): KCTD1 (ENSG00000134504), KCTD14 (ENSG00000151364), KCTD15 (ENSG00000153885), KCTD18 (ENSG00000155729), KCTD19 (ENSG00000168676), KCTD12 (ENSG00000178695), KCTD4 (ENSG00000180332), KCTD16 (ENSG00000183775), KCTD8 (ENSG00000183783), KCTD21 (ENSG00000188997), KCNRG (ENSG00000198553), KCTD11 (ENSG00000213859), KCTD7 (ENSG00000243335)

Protein

Protein identifiers

BTB/POZ domain-containing protein KCTD6 — Q8NC69 (reviewed: Q8NC69)

Alternative names: KCASH3 protein, Potassium channel tetramerization domain-containing protein 6

All UniProt accessions (3): A0A1D5RMQ6, Q8NC69, F5H7I0

UniProt curated annotations — full annotation on UniProt →

Function. Probable substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex mediating the ubiquitination and subsequent proteasomal degradation of target proteins. Promotes the ubiquitination of HDAC1; the function seems to depend on KCTD11:KCTD6 oligomerization. Can function as antagonist of the Hedgehog pathway by affecting the nuclear transfer of transcription factor GLI1; the function probably occurs via HDAC1 down-regulation, keeping GLI1 acetylated and inactive. Inhibits cell growth and tumorigenicity of medulloblastoma (MDB). Involved in regulating protein levels of ANK1 isoform Mu17 probably implicating CUL3-dependent proteasomal degradation.

Subunit / interactions. Homopentamer. Interacts with KCTD11; KCTD6 and KCTD11 may associate in pentameric assemblies. Interacts (via BTB domain) with CUL3; initially a 4:4 stoichiometry has been reported, however, electron microscopy revealed pentameric states with a five-pointed pinwheel shape. The interaction with CUL3 is indicative for a participation in a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex. Interacts with HDAC1; probably indirect as the interaction is requires the presence of KCTD11. Interacts with USP21 (preferentially catalytic inactive form). Interacts with ANK1 isoform Mu17; detected in striated muscle. Interacts with USP11.

Subcellular location. Cytoplasm. Myofibril. Sarcomere. M line.

Tissue specificity. Highly expressed in cerebellum and brain. Expression is down-regulated in medulloblastoma.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (2): NP_001121686, NP_699162 (=MANE)

Domains & families (InterPro)

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

Pfam: PF02214

UniProt features (7 total): region of interest 3, sequence conflict 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NC69-F1	87.43	0.67

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-8931987	RUNX1 regulates estrogen receptor mediated transcription
R-HSA-8951664	Neddylation
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-212436	Generic Transcription Pathway
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-8939211	ESR-mediated signaling
R-HSA-9006931	Signaling by Nuclear Receptors
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 131 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TGACCTY_ERR1_Q2, CTATGCA_MIR153, BILD_E2F3_ONCOGENIC_SIGNATURE, GOBP_NEGATIVE_REGULATION_OF_SMOOTHENED_SIGNALING_PATHWAY, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_REGULATION_OF_SMOOTHENED_SIGNALING_PATHWAY, GOBP_PROTEIN_HOMOOLIGOMERIZATION, BASAKI_YBX1_TARGETS_DN, GOBP_SMOOTHENED_SIGNALING_PATHWAY, DBP_Q6, OCT1_B

GO Biological Process (4): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), negative regulation of smoothened signaling pathway (GO:0045879), protein homooligomerization (GO:0051260)

GO Molecular Function (4): ankyrin binding (GO:0030506), identical protein binding (GO:0042802), cullin family protein binding (GO:0097602), protein binding (GO:0005515)

GO Cellular Component (3): cytosol (GO:0005829), M band (GO:0031430), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Transcriptional regulation by RUNX1	1
Post-translational protein modification	1
ESR-mediated signaling	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
RNA Polymerase II Transcription	1
Metabolism of proteins	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1
Signaling by Nuclear Receptors	1
Signal Transduction	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein binding	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
negative regulation of signal transduction	1
protein complex oligomerization	1
cytoskeletal protein binding	1
binding	1
cytoplasm	1
A band	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

668 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCTD6	CUL3	Q13618	874
KCTD6	CIT	O14578	594
KCTD6	MEI1	Q5TIA1	543
KCTD6	SPRYD3	Q8NCJ5	526
KCTD6	BTBD10	Q9BSF8	502
KCTD6	KCTD20	Q7Z5Y7	477
KCTD6	LCE5A	Q5TCM9	475
KCTD6	OR13C5	Q8NGS8	471
KCTD6	OBSCN	Q5VST9	445
KCTD6	ASB13	Q8WXK3	437
KCTD6	FBXO45	P0C2W1	418
KCTD6	KLHL25	Q9H0H3	402
KCTD6	FBXO32	Q969P5	399
KCTD6	OPRD1	P41143	397
KCTD6	ZSCAN29	Q8IWY8	396

IntAct

156 interactions, top by confidence:

A	B	Type	Score
CUL3	KCTD6	psi-mi:“MI:0915”(physical association)	0.870
KCTD6	CUL3	psi-mi:“MI:0915”(physical association)	0.870
KCTD6	CUL3	psi-mi:“MI:0407”(direct interaction)	0.870
PRPF31	KCTD6	psi-mi:“MI:0915”(physical association)	0.850
KCTD6	PRPF31	psi-mi:“MI:0915”(physical association)	0.850
KCTD6	KCTD6	psi-mi:“MI:0915”(physical association)	0.830
KCTD6	KCTD6	psi-mi:“MI:0407”(direct interaction)	0.830
GSDMD	KCTD6	psi-mi:“MI:0915”(physical association)	0.780
KCTD6	GSDMD	psi-mi:“MI:0915”(physical association)	0.780
KCTD6	EHHADH	psi-mi:“MI:0915”(physical association)	0.740
EHHADH	KCTD6	psi-mi:“MI:0915”(physical association)	0.740
KCTD6	SDCBP	psi-mi:“MI:0915”(physical association)	0.720
CDC23	KCTD6	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (102): KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid), KCTD6 (Two-hybrid)

ESM2 similar proteins: A3KMV1, A4IFB4, A5PKG7, A9ULR9, B1WC97, B5DEL1, O70479, O73916, P0C5J9, Q01820, Q0VD00, Q0VFV7, Q12259, Q13829, Q28DC9, Q2HJ48, Q2T9W0, Q2TUM3, Q3URF8, Q4G0X4, Q5EAX2, Q5F3E8, Q5M956, Q5RBH4, Q5XJ34, Q5ZJP7, Q6DC02, Q6DCX3, Q6DG99, Q6P3P4, Q6P7W2, Q719H9, Q7TNY1, Q7TPL3, Q7Z3E5, Q863D4, Q8BGV7, Q8BJK1, Q8BNL5, Q8K0E1

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.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neddylation	8	9.2×	2e-04
Antigen processing: Ubiquitination & Proteasome degradation	9	8.2×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	8	6.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

625 predictions. Top by Δscore:

Variant	Effect	Δscore
3:58492165:GCGCA:G	donor_gain	1.0000
3:58492167:GCA:G	donor_gain	1.0000
3:58492170:G:GG	donor_gain	1.0000
3:58498708:T:TA	acceptor_gain	1.0000
3:58498711:A:AG	acceptor_gain	1.0000
3:58498712:G:GG	acceptor_gain	1.0000
3:58498712:GT:G	acceptor_gain	1.0000
3:58498712:GTTTC:G	acceptor_gain	1.0000
3:58498782:GGTG:G	donor_loss	1.0000
3:58498783:G:GA	donor_loss	1.0000
3:58498784:T:A	donor_loss	1.0000
3:58500937:A:AG	acceptor_gain	1.0000
3:58500938:A:G	acceptor_gain	1.0000
3:58500943:CAGAT:C	acceptor_loss	1.0000
3:58500944:A:AG	acceptor_gain	1.0000
3:58500945:G:GG	acceptor_gain	1.0000
3:58500945:GAT:G	acceptor_gain	1.0000
3:58500945:GATGA:G	acceptor_gain	1.0000
3:58498709:GAAGT:G	acceptor_loss	0.9900
3:58498711:A:AC	acceptor_loss	0.9900
3:58498712:GTT:G	acceptor_gain	0.9900
3:58498712:GTTT:G	acceptor_gain	0.9900
3:58498783:G:GG	donor_gain	0.9900
3:58498785:GAGT:G	donor_loss	0.9900
3:58500944:AGAT:A	acceptor_gain	0.9900
3:58500945:GATG:G	acceptor_gain	0.9900
3:58492166:CGCA:C	donor_gain	0.9800
3:58492167:GCAG:G	donor_gain	0.9800
3:58492167:GCAGT:G	donor_loss	0.9800
3:58492168:CA:C	donor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000175041 (3:58492811 G>A), RS1000204706 (3:58492591 G>C), RS1000331495 (3:58500818 A>G,T), RS1000333753 (3:58501545 G>A,C), RS1000540148 (3:58493926 C>T), RS1000543551 (3:58494270 T>A), RS1000716393 (3:58502358 TAA>T), RS1000890251 (3:58493642 T>C,G), RS1000982464 (3:58502706 CTT>C), RS1001207257 (3:58491413 G>T), RS1001836388 (3:58500234 G>A), RS1001888742 (3:58500786 G>T), RS1001954591 (3:58492898 C>G,T), RS1002387424 (3:58493222 G>A,C), RS1002816894 (3:58490536 A>G)

Disease associations

OMIM: gene MIM:618791 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003945_9	Hepcidin/transferrin saturation ratio	7.000000e-07
GCST005752_17	Systemic lupus erythematosus	2.000000e-08
GCST007446_42	vWF levels	6.000000e-09
GCST007446_43	vWF levels	9.000000e-09
GCST007446_82	vWF levels	3.000000e-08
GCST007446_83	vWF levels	5.000000e-09
GCST010002_426	Refractive error	5.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007902	hepcidin:transferrin saturation ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
vanadyl sulfate	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	decreases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Quercetin	decreases expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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