KCTD16

Summary

KCTD16 (potassium channel tetramerization domain containing 16, HGNC:29244) is a protein-coding gene on chromosome 5q31.3, encoding BTB/POZ domain-containing protein KCTD16 (Q68DU8). 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 postsynaptic membrane potential; G protein-coupled neurotransmitter receptor activity involved in regulation of presynaptic membrane potential; and identical protein binding activity. Predicted to be involved in regulation of G protein-coupled receptor signaling pathway. Predicted to act upstream of or within behavioral fear response and memory. Predicted to be located in cell projection; plasma membrane; and synapse. Predicted to be part of receptor complex. Predicted to be active in postsynaptic membrane and presynaptic membrane.

Source: NCBI Gene 57528 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 52 total
• Druggable target: yes
• MANE Select transcript: NM_020768

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29244
Approved symbol	KCTD16
Name	potassium channel tetramerization domain containing 16
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1317
Ensembl gene	ENSG00000183775
Ensembl biotype	protein_coding
OMIM	613423
Entrez	57528

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000507359, ENST00000512467

RefSeq mRNA: 3 — MANE Select: NM_020768 NM_001370486, NM_001370487, NM_020768

CCDS: CCDS34260

Canonical transcript exons

ENST00000512467 — 4 exons

Exon	Start	End
ENSE00002021940	144174307	144174472
ENSE00002044092	144473660	144485686
ENSE00002079472	144170873	144171009
ENSE00002082947	144206389	144207546

Expression profiles

Bgee: expression breadth ubiquitous, 107 present calls, max score 88.36.

FANTOM5 (CAGE): breadth broad, TPM avg 4.9153 / max 174.7880, expressed in 621 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59180	3.3070	499
59183	0.5610	101
59179	0.4114	135
59176	0.2755	113
59181	0.1970	101
59182	0.1288	71
59184	0.0345	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	88.36	gold quality
endothelial cell	CL:0000115	86.69	gold quality
primary visual cortex	UBERON:0002436	83.52	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.49	gold quality
occipital lobe	UBERON:0002021	82.50	gold quality
superior frontal gyrus	UBERON:0002661	82.50	gold quality
parietal lobe	UBERON:0001872	80.61	gold quality
postcentral gyrus	UBERON:0002581	80.52	gold quality
entorhinal cortex	UBERON:0002728	78.73	gold quality
prefrontal cortex	UBERON:0000451	78.65	gold quality
middle temporal gyrus	UBERON:0002771	78.00	gold quality
frontal cortex	UBERON:0001870	76.50	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	75.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.79	gold quality
epithelial cell of pancreas	CL:0000083	75.70	silver quality
neocortex	UBERON:0001950	75.38	gold quality
cerebral cortex	UBERON:0000956	74.80	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.19	gold quality
lateral nuclear group of thalamus	UBERON:0002736	72.00	gold quality
anterior cingulate cortex	UBERON:0009835	71.75	gold quality
ganglionic eminence	UBERON:0004023	71.45	gold quality
temporal lobe	UBERON:0001871	71.20	gold quality
Ammon’s horn	UBERON:0001954	71.14	gold quality
right frontal lobe	UBERON:0002810	69.98	gold quality
forebrain	UBERON:0001890	68.63	gold quality
stromal cell of endometrium	CL:0002255	68.02	gold quality
caudate nucleus	UBERON:0001873	66.25	gold quality
amygdala	UBERON:0001876	66.16	gold quality
brain	UBERON:0000955	64.78	gold quality
nucleus accumbens	UBERON:0001882	64.69	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	2843.13
E-HCAD-35	yes	2600.42
E-ANND-3	yes	6.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CHD4

miRNA regulators (miRDB)

161 targeting KCTD16, 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-5011-5P	100.00	83.46	5820
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-6740-5P	100.00	65.64	932
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
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-3692-3P	99.98	70.27	2139
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504

Literature-anchored findings (GeneRIF, showing 1)

• Investigated structure/interaction of GABAB receptors and potassium channel tetramerization domain containing 16 (KCTD16). Found that mutating certain conserved KCTD16 interfacial residues disrupted modulation of GABAB receptors, suggesting a common mode of KCTD interaction with GABAB receptors. (PMID:30971491)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	kctd16a	ENSDARG00000004648
danio_rerio	kctd16b	ENSDARG00000020102
mus_musculus	Kctd16	ENSMUSG00000051401
rattus_norvegicus	Kctd16	ENSRNOG00000084971
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), KCTD8 (ENSG00000183783), KCTD21 (ENSG00000188997), KCNRG (ENSG00000198553), KCTD11 (ENSG00000213859), KCTD7 (ENSG00000243335)

Protein

Protein identifiers

BTB/POZ domain-containing protein KCTD16 — Q68DU8 (reviewed: Q68DU8)

Alternative names: Potassium channel tetramerization domain-containing protein 16

All UniProt accessions (1): Q68DU8

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. Homopentamer; forms an open pentamer. In contrast to other BTB domain-containing proteins, does not interact with CUL3. Interacts as a tetramer with GABRB1 and GABRB2.

Subcellular location. Presynaptic cell membrane. Postsynaptic cell membrane.

RefSeq proteins (3): NP_001357415, NP_001357416, NP_065819* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR003131	T1-type_BTB	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR049903	H1_KCTD16	Domain
IPR057093	H1_KCTD8_12_16	Domain

Pfam: PF02214, PF23110

UniProt features (24 total): helix 8, strand 8, modified residue 5, chain 1, domain 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6QB7	X-RAY DIFFRACTION	2.23
6OCR	X-RAY DIFFRACTION	2.28
6I0Q	X-RAY DIFFRACTION	2.3
6OCP	X-RAY DIFFRACTION	2.35
5A15	X-RAY DIFFRACTION	2.76
6OCT	X-RAY DIFFRACTION	2.8
6M8R	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q68DU8-F1	70.38	0.37

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 (5): 112, 130, 137, 143, 146

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 90 (showing top): GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_MULTICELLULAR_ORGANISMAL_RESPONSE_TO_STRESS, GOBP_FEAR_RESPONSE, CORRE_MULTIPLE_MYELOMA_UP, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GOCC_POSTSYNAPSE, chr5q31, GOCC_SYNAPSE, GOCC_POSTSYNAPTIC_MEMBRANE, GOCC_PRESYNAPTIC_MEMBRANE, GOCC_RECEPTOR_COMPLEX, GOCC_PLASMA_MEMBRANE_REGION, GOCC_PRESYNAPSE

GO Biological Process (6): behavioral fear response (GO:0001662), memory (GO:0007613), regulation of G protein-coupled receptor signaling pathway (GO:0008277), protein homooligomerization (GO:0051260), regulation of postsynaptic membrane potential (GO:0060078), regulation of presynaptic membrane potential (GO:0099505)

GO Molecular Function (4): identical protein binding (GO:0042802), obsolete G protein-coupled neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential (GO:0099579), obsolete G protein-coupled neurotransmitter receptor activity involved in regulation of presynaptic membrane potential (GO:0150047), protein binding (GO:0005515)

GO Cellular Component (7): presynaptic membrane (GO:0042734), signaling receptor complex (GO:0043235), postsynaptic membrane (GO:0045211), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of membrane potential	2
synaptic membrane	2
cellular anatomical structure	2
behavioral defense response	1
fear response	1
learning or memory	1
G protein-coupled receptor signaling pathway	1
regulation of signal transduction	1
protein complex oligomerization	1
protein binding	1
binding	1
presynapse	1
protein-containing complex	1
postsynapse	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

740 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCTD16	CUL3	Q13618	596
KCTD16	KCTD20	Q7Z5Y7	512
KCTD16	KCTD19	Q17RG1	475
KCTD16	CACNA1B	Q00975	475
KCTD16	BTBD10	Q9BSF8	453
KCTD16	TMEM236	Q5W0B7	448
KCTD16	KCTD11	Q693B1	415
KCTD16	RND2	P52198	414
KCTD16	KCTD8	Q6ZWB6	410
KCTD16	YIPF5	Q969M3	392
KCTD16	TMT1B	Q6UX53	382
KCTD16	NTRK2	Q16620	370
KCTD16	PLAC8L1	A1L4L8	370
KCTD16	SUOX	P51687	345
KCTD16	KCTD9	Q7L273	340

IntAct

20 interactions, top by confidence:

A	B	Type	Score
KCTD16	GABBR2	psi-mi:“MI:0407”(direct interaction)	0.640
GABBR2	KCTD16	psi-mi:“MI:0407”(direct interaction)	0.640
HAL	KCTD16	psi-mi:“MI:0914”(association)	0.530
APP	KCTD16	psi-mi:“MI:0915”(physical association)	0.510
KCTD16	KCTD16	psi-mi:“MI:0407”(direct interaction)	0.440
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
RIMS1	PSMD12	psi-mi:“MI:0914”(association)	0.350
HCN1	USP27X	psi-mi:“MI:0914”(association)	0.350
GNG2	FAM171A2	psi-mi:“MI:0914”(association)	0.350
ZFP69B	CNP	psi-mi:“MI:0914”(association)	0.350
KCTD16	SMAD3	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
KCTD12	CYTH3	psi-mi:“MI:0914”(association)	0.350
	NFIB	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): KCTD16 (Affinity Capture-MS), KCTD16 (Two-hybrid), APP (Affinity Capture-Western), KCTD16 (Affinity Capture-Western), KCTD16 (Affinity Capture-MS), GABBR2 (Co-crystal Structure), KCTD16 (Reconstituted Complex), GABBR2 (Reconstituted Complex), KCTD16 (Affinity Capture-Western), KCTD16 (Affinity Capture-MS), SMAD3 (Affinity Capture-MS), KCTD16 (Affinity Capture-MS), KCTD16 (Affinity Capture-MS), KCTD12 (Affinity Capture-MS), KCTD16 (Positive Genetic)

ESM2 similar proteins: A0A7P0TBJ1, A0A804C8T0, A2AQ25, A2BE76, A4IIZ9, A6H7A8, B5DF41, E9PSK7, F4HRI2, I6PL68, O60271, P49140, P68943, Q0V989, Q14AM7, Q14CZ0, Q1JPG0, Q28HY5, Q2TBN4, Q4QQM5, Q4V872, Q50H33, Q58A65, Q5DTY9, Q5EY87, Q5R595, Q5RAR8, Q5RHQ8, Q5RKN3, Q61909, Q62739, Q68DU8, Q6PAX8, Q6PCP5, Q7SZQ4, Q80U23, Q8CID0, Q8NAN2, Q8QFP1, Q91Y53

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3556 predictions. Top by Δscore:

Variant	Effect	Δscore
5:144170997:TGCTA:T	donor_gain	1.0000
5:144171004:GT:G	donor_gain	1.0000
5:144171006:GTTT:G	donor_gain	1.0000
5:144171010:G:GG	donor_gain	1.0000
5:144174305:A:AG	acceptor_gain	1.0000
5:144174306:G:GA	acceptor_gain	1.0000
5:144383054:T:A	acceptor_gain	1.0000
5:144473657:CAGG:C	acceptor_loss	1.0000
5:144473658:A:AT	acceptor_loss	1.0000
5:144473658:AG:A	acceptor_gain	1.0000
5:144473658:AGGT:A	acceptor_gain	1.0000
5:144473659:GG:G	acceptor_gain	1.0000
5:144473659:GGT:G	acceptor_gain	1.0000
5:144473659:GGTG:G	acceptor_gain	1.0000
5:144473659:GGTGA:G	acceptor_gain	1.0000
5:144170969:GTC:G	donor_gain	0.9900
5:144170998:GCTAA:G	donor_gain	0.9900
5:144174306:GTT:G	acceptor_gain	0.9900
5:144174306:GTTC:G	acceptor_gain	0.9900
5:144174468:CCAAT:C	donor_gain	0.9900
5:144174471:AT:A	donor_gain	0.9900
5:144174473:G:GG	donor_gain	0.9900
5:144252790:A:T	donor_gain	0.9900
5:144366635:G:GA	donor_gain	0.9900
5:144371603:C:CG	donor_gain	0.9900
5:144383052:A:AG	acceptor_gain	0.9900
5:144383052:ACT:A	acceptor_gain	0.9900
5:144383053:C:G	acceptor_gain	0.9900
5:144437357:G:GG	donor_gain	0.9900
5:144473658:A:AG	acceptor_gain	0.9900

AlphaMissense

2818 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:144206800:T:A	L29Q	1.000
5:144206800:T:C	L29P	1.000
5:144206804:T:A	N30K	1.000
5:144206804:T:G	N30K	1.000
5:144206806:T:A	V31D	1.000
5:144206808:G:A	G32R	1.000
5:144206808:G:C	G32R	1.000
5:144206808:G:T	G32W	1.000
5:144206809:G:A	G32E	1.000
5:144206809:G:T	G32V	1.000
5:144206811:G:C	G33R	1.000
5:144206812:G:A	G33D	1.000
5:144206820:T:C	Y36H	1.000
5:144206820:T:G	Y36D	1.000
5:144206934:T:C	F74L	1.000
5:144206935:T:C	F74S	1.000
5:144206936:C:A	F74L	1.000
5:144206936:C:G	F74L	1.000
5:144206944:G:C	R77T	1.000
5:144206944:G:T	R77I	1.000
5:144206945:A:C	R77S	1.000
5:144206945:A:T	R77S	1.000
5:144206946:G:C	D78H	1.000
5:144206947:A:C	D78A	1.000
5:144206947:A:G	D78G	1.000
5:144206947:A:T	D78V	1.000
5:144206948:T:A	D78E	1.000
5:144206948:T:G	D78E	1.000
5:144206949:G:A	G79R	1.000
5:144206949:G:C	G79R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001420 (5:144403161 C>A), RS1000002554 (5:144184763 A>G), RS1000011600 (5:144227840 A>G), RS1000012086 (5:144420213 A>G), RS1000013796 (5:144271882 G>A), RS1000015521 (5:144175822 C>T), RS1000025981 (5:144486109 C>A), RS1000026599 (5:144281459 T>C), RS1000028667 (5:144407315 A>G,T), RS1000031018 (5:144448262 A>G), RS1000033662 (5:144185062 C>A,G), RS1000034435 (5:144219274 C>T), RS1000039990 (5:144212264 A>C,G), RS1000040135 (5:144406932 C>T), RS1000045746 (5:144463513 T>C)

Disease associations

OMIM: gene MIM:613423 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002337_8	Amyotrophic lateral sclerosis (sporadic)	8.000000e-06
GCST003992_13	Photic sneeze reflex	4.000000e-09
GCST007328_55	Alcohol consumption (drinks per week)	4.000000e-08
GCST008258_16	Alcohol use disorder (consumption score)	2.000000e-08
GCST008522_9	Bitter alcoholic beverage consumption	8.000000e-08
GCST008660_3	Lung function in never smokers (high FEV1 vs average FEV1)	2.000000e-07
GCST009173_1	Response to (pegylated) interferon in HBeAG-positive hepatitis B	3.000000e-06
GCST009391_1837	Metabolite levels	8.000000e-06
GCST009391_345	Metabolite levels	8.000000e-06
GCST009391_70	Metabolite levels	5.000000e-06
GCST010002_40	Refractive error	2.000000e-13
GCST011494_24	Daytime nap	2.000000e-14

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0009458	alcohol use disorder measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004314	forced expiratory volume
EFO:0007859	response to interferon
EFO:0010412	triacylglycerol 50:5 measurement
EFO:0010431	triacylglycerol 56:4 measurement
EFO:0010353	diacylglycerol 34:2 measurement
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523340 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, increases methylation	2
methyleugenol	decreases expression	1
trichostatin A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	increases reaction, affects binding	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
Benzo(a)pyrene	increases methylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Oxygen	increases expression	1
Phenobarbital	decreases expression	1
Polychlorinated Biphenyls	affects expression	1
Silicon Dioxide	decreases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4322702	Binding	Displacement of TAMRA-AAG-SLQLPILHHAYLPSIGGV from recombinant 6X His tagged KCTD16 T1 domain (unknown origin) 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.