KCTD21

Summary

KCTD21 (potassium channel tetramerization domain containing 21, HGNC:27452) is a protein-coding gene on chromosome 11q14.1, encoding BTB/POZ domain-containing protein KCTD21 (Q4G0X4). 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 cullin family protein binding activity; histone deacetylase binding activity; and identical protein binding activity. Involved in negative regulation of smoothened signaling pathway and ubiquitin-dependent protein catabolic process.

Source: NCBI Gene 283219 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 41 total
• MANE Select transcript: NM_001029859

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27452
Approved symbol	KCTD21
Name	potassium channel tetramerization domain containing 21
Location	11q14.1
Locus type	gene with protein product
Status	Approved
Aliases	KCASH2
Ensembl gene	ENSG00000188997
Ensembl biotype	protein_coding
OMIM	618790
Entrez	283219

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 13 protein_coding

ENST00000340067, ENST00000525447, ENST00000526208, ENST00000528776, ENST00000529350, ENST00000530018, ENST00000908679, ENST00000908680, ENST00000908681, ENST00000908682, ENST00000920356, ENST00000941221, ENST00000941222

RefSeq mRNA: 1 — MANE Select: NM_001029859 NM_001029859

CCDS: CCDS31645

Canonical transcript exons

ENST00000340067 — 2 exons

Exon	Start	End
ENSE00001379270	78171249	78174583
ENSE00002198811	78188573	78188626

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 88.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.2936 / max 26.9472, expressed in 1656 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121468	4.2936	1656

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	88.43	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.72	silver quality
left ventricle myocardium	UBERON:0006566	86.69	silver quality
right adrenal gland cortex	UBERON:0035827	85.68	gold quality
right adrenal gland	UBERON:0001233	85.62	gold quality
amniotic fluid	UBERON:0000173	85.56	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.51	gold quality
left adrenal gland	UBERON:0001234	84.67	gold quality
lower esophagus mucosa	UBERON:0035834	84.52	gold quality
left adrenal gland cortex	UBERON:0035825	84.10	gold quality
right lobe of liver	UBERON:0001114	84.08	gold quality
adrenal cortex	UBERON:0001235	84.00	gold quality
adrenal gland	UBERON:0002369	83.98	gold quality
adrenal tissue	UBERON:0018303	83.77	gold quality
upper arm skin	UBERON:0004263	83.60	gold quality
stromal cell of endometrium	CL:0002255	83.28	gold quality
popliteal artery	UBERON:0002250	83.18	gold quality
tibial artery	UBERON:0007610	83.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.93	gold quality
gingival epithelium	UBERON:0001949	82.32	gold quality
aorta	UBERON:0000947	81.94	gold quality
right coronary artery	UBERON:0001625	81.69	gold quality
liver	UBERON:0002107	81.63	gold quality
granulocyte	CL:0000094	81.62	gold quality
substantia nigra	UBERON:0002038	81.42	gold quality
islet of Langerhans	UBERON:0000006	81.33	gold quality
midbrain	UBERON:0001891	80.97	gold quality
prefrontal cortex	UBERON:0000451	80.95	gold quality
blood	UBERON:0000178	80.84	gold quality
esophagus mucosa	UBERON:0002469	80.83	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

133 targeting KCTD21, 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-3924	100.00	72.09	2394
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
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-3688-3P	99.97	72.02	2834
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6778-3P	99.96	67.29	2693

Literature-anchored findings (GeneRIF, showing 1)

• 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)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kctd21	ENSMUSG00000044952
rattus_norvegicus	Kctd21	ENSRNOG00000024793
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), KCTD8 (ENSG00000183783), KCNRG (ENSG00000198553), KCTD11 (ENSG00000213859), KCTD7 (ENSG00000243335)

Protein

Protein identifiers

BTB/POZ domain-containing protein KCTD21 — Q4G0X4 (reviewed: Q4G0X4)

Alternative names: KCASH2 protein, Potassium channel tetramerization domain-containing protein 21

All UniProt accessions (6): E9PJJ5, E9PK99, E9PM10, E9PMS5, E9PRT1, Q4G0X4

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. 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).

Subunit / interactions. Homopentamer. Interacts with KCTD11; KCTD21 and KCTD11 may associate in pentameric assemblies. Interacts (via BTB domain) with CUL3; indicative for a participation in a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex.

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

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_001025030* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR003131	T1-type_BTB	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR045763	KCTD11/21_C	Domain

Pfam: PF02214, PF19329

UniProt features (5 total): chain 1, domain 1, coiled-coil region 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4G0X4-F1	89.52	0.69

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
85–87	abolishes interaction with cul3.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 113 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_SMOOTHENED_SIGNALING_PATHWAY, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_REGULATION_OF_SMOOTHENED_SIGNALING_PATHWAY, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GOBP_SMOOTHENED_SIGNALING_PATHWAY, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GOBP_PROTEIN_CATABOLIC_PROCESS, CTGAGCC_MIR24, GOBP_PROTEOLYSIS, GOMF_HISTONE_DEACETYLASE_BINDING, GOMF_CULLIN_FAMILY_PROTEIN_BINDING, GOBP_PROTEIN_COMPLEX_OLIGOMERIZATION, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BROWN_UP

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): identical protein binding (GO:0042802), histone deacetylase binding (GO:0042826), cullin family protein binding (GO:0097602), protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
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
enzyme binding	1
binding	1

Protein interactions and networks

STRING

498 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCTD21	CUL3	Q13618	668
KCTD21	KCTD20	Q7Z5Y7	508
KCTD21	BTBD10	Q9BSF8	508
KCTD21	ALG8	Q9BVK2	471
KCTD21	OR6C65	A6NJZ3	447
KCTD21	KCTD9	Q7L273	419
KCTD21	USP35	Q9P2H5	408
KCTD21	KCTD5	Q9NXV2	381
KCTD21	TENM4	Q6N022	372
KCTD21	KCTD17	Q8N5Z5	361
KCTD21	GAB2	Q9UQC2	351
KCTD21	KCTD3	Q9Y597	345
KCTD21	KCTD8	Q6ZWB6	345
KCTD21	KCTD12	Q96CX2	344
KCTD21	DNAJC28	Q9NX36	340

IntAct

62 interactions, top by confidence:

A	B	Type	Score
DNAJB11	HSPA5	psi-mi:“MI:0914”(association)	0.830
KCTD21	KCTD21	psi-mi:“MI:0915”(physical association)	0.680
KCTD21	ZMYND19	psi-mi:“MI:0915”(physical association)	0.670
ZMYND19	TNFAIP1	psi-mi:“MI:0914”(association)	0.670
UFM1	KCTD21	psi-mi:“MI:0915”(physical association)	0.560
KCTD21	C22orf15	psi-mi:“MI:0915”(physical association)	0.560
KCTD21	RNF25	psi-mi:“MI:0915”(physical association)	0.560
KCTD21	NMRK1	psi-mi:“MI:0915”(physical association)	0.560
KCTD21	CRLF3	psi-mi:“MI:0915”(physical association)	0.560
KCTD21	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
PPL	KCTD21	psi-mi:“MI:0915”(physical association)	0.560
LONRF1	KCTD21	psi-mi:“MI:0915”(physical association)	0.560
CUL3	RHOBTB1	psi-mi:“MI:0914”(association)	0.530
TRIB2	POTEF	psi-mi:“MI:0914”(association)	0.530
MRGBP	KPNA4	psi-mi:“MI:0914”(association)	0.530
DOC2A	DOC2B	psi-mi:“MI:0914”(association)	0.530
KLHL14	KCTD21	psi-mi:“MI:0914”(association)	0.530
KCTD21	KCTD11	psi-mi:“MI:0915”(physical association)	0.400
KCTD6	KCTD21	psi-mi:“MI:0915”(physical association)	0.400
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
DUSP22	POTEF	psi-mi:“MI:0914”(association)	0.350
LILRB3	FAM171A2	psi-mi:“MI:0914”(association)	0.350
WDFY1	HMMR	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
ANKRD39	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (56): KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KCTD21 (Affinity Capture-Western), KCTD21 (Two-hybrid), KCTD21 (Two-hybrid), KCTD21 (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 42 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
Antigen processing: Ubiquitination & Proteasome degradation	5	8.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	38
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

509 predictions. Top by Δscore:

Variant	Effect	Δscore
11:78174580:AGTC:A	acceptor_gain	1.0000
11:78174581:GTC:G	acceptor_gain	1.0000
11:78174581:GTCC:G	acceptor_loss	1.0000
11:78174582:TC:T	acceptor_gain	1.0000
11:78174583:CC:C	acceptor_gain	1.0000
11:78174584:C:CC	acceptor_gain	1.0000
11:78174585:T:G	acceptor_loss	1.0000
11:78174579:TAGTC:T	acceptor_gain	0.9900
11:78174593:G:C	acceptor_gain	0.9900
11:78188574:T:TA	donor_gain	0.9900
11:78188598:C:CA	donor_gain	0.9900
11:78174581:GTCCT:G	acceptor_gain	0.9800
11:78174582:TCCTG:T	acceptor_gain	0.9800
11:78174593:G:GC	acceptor_gain	0.9800
11:78174580:AGTCC:A	acceptor_gain	0.9700
11:78174583:CCTGG:C	acceptor_gain	0.9700
11:78188568:CCCA:C	donor_loss	0.9700
11:78188569:CCAC:C	donor_loss	0.9700
11:78188570:CA:C	donor_loss	0.9700
11:78188571:ACCT:A	donor_gain	0.9700
11:78188571:ACCTC:A	donor_loss	0.9700
11:78188572:CCTC:C	donor_gain	0.9700
11:78174584:C:A	acceptor_gain	0.9600
11:78174584:C:T	acceptor_gain	0.9500
11:78186679:A:AC	donor_gain	0.9500
11:78186680:C:CC	donor_gain	0.9500
11:78188567:ACCC:A	donor_loss	0.9500
11:78174585:T:A	acceptor_gain	0.9300
11:78188620:G:C	donor_gain	0.9000
11:78188597:T:A	donor_gain	0.8400

AlphaMissense

1740 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:78174297:G:C	F86L	1.000
11:78174297:G:T	F86L	1.000
11:78174299:A:G	F86L	1.000
11:78174403:C:G	R51P	1.000
11:78173993:A:G	W188R	0.999
11:78173993:A:T	W188R	0.999
11:78174305:C:G	A84P	0.999
11:78174367:A:G	L63P	0.999
11:78174369:G:C	F62L	0.999
11:78174369:G:T	F62L	0.999
11:78174371:A:G	F62L	0.999
11:78174376:A:G	L60P	0.999
11:78174387:G:C	F56L	0.999
11:78174387:G:T	F56L	0.999
11:78174388:A:G	F56S	0.999
11:78174389:A:G	F56L	0.999
11:78174400:T:A	D52V	0.999
11:78174401:C:G	D52H	0.999
11:78174409:A:T	I49N	0.999
11:78174493:A:G	L21P	0.999
11:78174526:C:A	G10V	0.999
11:78174526:C:T	G10E	0.999
11:78174527:C:A	G10W	0.999
11:78174527:C:G	G10R	0.999
11:78174527:C:T	G10R	0.999
11:78174529:A:T	V9D	0.999
11:78173848:A:G	F236S	0.998
11:78173991:C:A	W188C	0.998
11:78173991:C:G	W188C	0.998
11:78174220:A:G	L112P	0.998

dbSNP variants (sampled 300 via entrez): RS1000338851 (11:78187227 CTT>C), RS1000533104 (11:78170974 C>T), RS1000916564 (11:78178330 A>C,T), RS1000957331 (11:78177477 G>A), RS1000960685 (11:78182024 G>A), RS1000992908 (11:78187454 G>A), RS1001266610 (11:78188219 C>A,T), RS1001278252 (11:78188649 C>A,T), RS1001375840 (11:78188575 C>A,G,T), RS1001504538 (11:78177372 G>A), RS1001959444 (11:78178702 G>C), RS1002037644 (11:78188969 G>T), RS1002080818 (11:78173067 C>A,T), RS1002148505 (11:78171790 G>A), RS1002347608 (11:78189153 G>C)

Disease associations

OMIM: gene MIM:618790 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007277_15	Tourette syndrome	5.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
Cadmium Chloride	decreases expression, increases abundance	3
(+)-JQ1 compound	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
tetrabromobisphenol A	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
Cadmium	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Folic Acid	decreases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	increases expression	1
Gold Compounds	decreases expression, increases methylation	1
tert-Butylhydroperoxide	affects expression	1
Vitamin K 3	affects expression	1

Clinical trials (associated diseases)

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