KLHL14

Summary

KLHL14 (kelch like family member 14, HGNC:29266) is a protein-coding gene on chromosome 18q12.1, encoding Kelch-like protein 14 (Q9P2G3).

The protein encoded by this gene is a member of the Kelch-like gene family, whose members contain a BTB/POZ domain, a BACK domain, and several Kelch domains. The encoded protein possesses six Kelch domains and localizes to the endoplasmic reticulum, where it interacts with torsin-1A.

Source: NCBI Gene 57565 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 67 total
• Druggable target: yes
• MANE Select transcript: NM_020805

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29266
Approved symbol	KLHL14
Name	kelch like family member 14
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1384
Ensembl gene	ENSG00000197705
Ensembl biotype	protein_coding
OMIM	613772
Entrez	57565

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000358095, ENST00000359358, ENST00000583263, ENST00000891553, ENST00000891554, ENST00000913100

RefSeq mRNA: 1 — MANE Select: NM_020805 NM_020805

CCDS: CCDS32813

Canonical transcript exons

ENST00000359358 — 9 exons

Exon	Start	End
ENSE00001400609	32769645	32770634
ENSE00001402907	32672673	32674797
ENSE00001409458	32677173	32677330
ENSE00001422669	32687155	32687233
ENSE00001425747	32695463	32695552
ENSE00001427230	32741928	32742049
ENSE00001494892	32772667	32773023
ENSE00001506059	32680169	32680327
ENSE00001506061	32680409	32680599

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 93.23.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0047 / max 111.6535, expressed in 210 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171604	0.4839	150
171602	0.2366	117
171603	0.0975	57
171606	0.0796	39
171607	0.0664	35
171608	0.0408	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	93.23	gold quality
seminal vesicle	UBERON:0000998	91.93	gold quality
right uterine tube	UBERON:0001302	85.96	gold quality
cortical plate	UBERON:0005343	85.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.00	gold quality
buccal mucosa cell	CL:0002336	80.57	silver quality
right lobe of thyroid gland	UBERON:0001119	79.75	gold quality
thyroid gland	UBERON:0002046	79.44	gold quality
fallopian tube	UBERON:0003889	79.41	gold quality
left lobe of thyroid gland	UBERON:0001120	78.44	gold quality
spleen	UBERON:0002106	77.23	gold quality
bone marrow cell	CL:0002092	76.15	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.84	gold quality
metanephros	UBERON:0000081	75.67	gold quality
ileal mucosa	UBERON:0000331	72.25	gold quality
lymph node	UBERON:0000029	71.83	gold quality
metanephros cortex	UBERON:0010533	71.16	gold quality
renal medulla	UBERON:0000362	69.86	gold quality
bone marrow	UBERON:0002371	68.81	gold quality
adult mammalian kidney	UBERON:0000082	67.01	gold quality
kidney	UBERON:0002113	66.69	gold quality
vermiform appendix	UBERON:0001154	65.43	gold quality
ventricular zone	UBERON:0003053	64.76	gold quality
caput epididymis	UBERON:0004358	64.38	gold quality
endometrium	UBERON:0001295	64.11	gold quality
left uterine tube	UBERON:0001303	63.15	gold quality
adrenal tissue	UBERON:0018303	62.70	gold quality
ganglionic eminence	UBERON:0004023	62.68	gold quality
body of uterus	UBERON:0009853	62.64	gold quality
endocervix	UBERON:0000458	62.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

169 targeting KLHL14, 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-190A-3P	100.00	80.35	5520
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-6873-3P	100.00	71.42	2626
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-6077	99.99	68.04	2299
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-651-3P	99.94	73.48	5177

Literature-anchored findings (GeneRIF, showing 3)

• Printor is a torsinA-interacting protein implicated in dystonia pathogenesis (PMID:19535332)
• TorsinA ATP hydrolysis is induced upon association with LAP1 and LULL1, type II transmembrane proteins residing in the nuclear envelope and endoplasmic reticulum. (PMID:23569223)
• Novel tumor suppressor, KLHL14, is a subunit of a ubiquitin ligase that associates with the endoplasmic reticulum-associated protein degradation machinery. KLHL14 promotes ubiquitylation of B cell receptor (BCR) subunits and decreases the stability of immature BCR glycoforms in the endoplasmic reticulum, thereby reducing BCR levels. Conversely, loss of KLHL14 promotes BCR-dependent NF-kappaB activation and survival. (PMID:32127472)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl14	ENSDARG00000045275
mus_musculus	Klhl14	ENSMUSG00000042514
rattus_norvegicus	Klhl14	ENSRNOG00000015418

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359)

Protein

Protein identifiers

Kelch-like protein 14 — Q9P2G3 (reviewed: Q9P2G3)

Alternative names: Protein interactor of Torsin-1A

All UniProt accessions (2): Q9P2G3, J3QQM3

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with TOR1A, preferentially with the ATP-free form.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum membrane.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P2G3-1	1	yes
Q9P2G3-2	2

RefSeq proteins (1): NP_065856* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family
IPR030584	KLHL14_BTB_POZ	Domain
IPR047027	KLHL14_BACK	Domain

Pfam: PF00651, PF01344, PF07707, PF24681

UniProt features (13 total): repeat 6, domain 2, splice variant 2, chain 1, compositionally biased region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2G3-F1	88.04	0.75

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 143 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, chr18q12, ACTTTAT_MIR1425P, GOCC_NEURON_PROJECTION, CCCAGAG_MIR326, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, BREDEMEYER_RAG_SIGNALING_NOT_VIA_ATM_UP, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_TRANSFERASE_COMPLEX, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOBP_PROTEOLYSIS, GOCC_CELL_BODY, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX, GOCC_SOMATODENDRITIC_COMPARTMENT

GO Biological Process (0):

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

GO Cellular Component (9): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), actin cytoskeleton (GO:0015629), aggresome (GO:0016235), neuron projection (GO:0043005), neuronal cell body (GO:0043025), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoskeleton	1
inclusion body	1
plasma membrane bounded cell projection	1
somatodendritic compartment	1
cell body	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

572 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL14	TOR1A	O14656	531
KLHL14	SYT8	Q8NBV8	440
KLHL14	RMP24	Q32NC0	399
KLHL14	TOR1AIP2	Q8NFQ8	392
KLHL14	TACC2	O95359	388
KLHL14	RBMS3	Q6XE24	388
KLHL14	C5orf58	C9J3I9	371
KLHL14	OAF	Q86UD1	363
KLHL14	PRELID3A	Q96N28	356
KLHL14	L2HGDH	Q9H9P8	354
KLHL14	FLYWCH2	Q96CP2	353
KLHL14	PKHD1L1	Q86WI1	347
KLHL14	OSBPL10	Q9BXB5	334
KLHL14	SLC26A7	Q8TE54	327
KLHL14	D2HGDH	Q8N465	326

IntAct

14 interactions, top by confidence:

A	B	Type	Score
KLHL14	KCTD21	psi-mi:“MI:0914”(association)	0.530
KLHL14	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
ALG3	GFAP	psi-mi:“MI:0914”(association)	0.350
KLHL28	PRKACB	psi-mi:“MI:0914”(association)	0.350
TOP3B	PRMT5	psi-mi:“MI:0914”(association)	0.350
ZBTB24	BACH1	psi-mi:“MI:0914”(association)	0.350
IGHV4-31	IGHG2	psi-mi:“MI:0914”(association)	0.350
PAX5	PAX8	psi-mi:“MI:0914”(association)	0.350
KLHL14	ARHGAP32	psi-mi:“MI:0914”(association)	0.350

BioGRID (81): FBXL17 (Affinity Capture-MS), FLAD1 (Affinity Capture-MS), NUDCD3 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KLHL14 (Affinity Capture-MS), KLHL14 (Affinity Capture-MS), KLHL14 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), FBXL17 (Affinity Capture-MS), FLAD1 (Affinity Capture-MS), NUDCD3 (Affinity Capture-MS), KLHL14 (Affinity Capture-RNA), KLHL14 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B8YAB1, B1H285, B3DIV9, E9QIN8, E9QJ30, F1QEG2, O88879, Q08CL3, Q08CY1, Q0D2A9, Q13939, Q28068, Q3UQV5, Q3ZCT8, Q503R4, Q5F3N5, Q5R4S6, Q5R663, Q5RG82, Q5XHZ6, Q5XI58, Q5ZI33, Q69ZK5, Q6DFF7, Q6DFU2, Q6Q7X9, Q6V595, Q7ZVQ8, Q86V97, Q8BHI4, Q8BUL5, Q8BWA5, Q8CA72, Q8CDE2, Q8CE33, Q8IXQ5, Q8NAB2, Q8NFY9, Q8R179, Q8WVZ9

Diamond homologs: A0JN76, A1YPR0, A6QQY2, B0WWP2, B1WBS3, B2RXF5, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, C9JR72, D2HEW7, D3ZZC3, E0CZ16, E9Q4F2, F1LZ52, F1MBP6, O14867, O15062, O43167, O88282, O88939, O93567, O94889, O95365, P97302, P97303, Q08CY1, Q0IJ29, Q0P4X6, Q13105, Q16RL8, Q1L8W0, Q2M0J9

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	58
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1715 predictions. Top by Δscore:

Variant	Effect	Δscore
18:32674793:GCCCC:G	acceptor_gain	1.0000
18:32674794:CCCC:C	acceptor_gain	1.0000
18:32674794:CCCCC:C	acceptor_gain	1.0000
18:32674795:CCC:C	acceptor_gain	1.0000
18:32674795:CCCC:C	acceptor_gain	1.0000
18:32674796:CC:C	acceptor_gain	1.0000
18:32674796:CCC:C	acceptor_gain	1.0000
18:32674796:CCCTG:C	acceptor_loss	1.0000
18:32674797:CC:C	acceptor_gain	1.0000
18:32674798:C:A	acceptor_loss	1.0000
18:32674798:C:CC	acceptor_gain	1.0000
18:32674799:T:G	acceptor_loss	1.0000
18:32677172:CCATA:C	donor_gain	1.0000
18:32680182:T:TA	donor_gain	1.0000
18:32680595:CTCTT:C	acceptor_gain	1.0000
18:32680597:CTT:C	acceptor_gain	1.0000
18:32680598:TT:T	acceptor_gain	1.0000
18:32680600:C:CC	acceptor_gain	1.0000
18:32687150:CTTA:C	donor_loss	1.0000
18:32687151:TTAC:T	donor_loss	1.0000
18:32687152:TA:T	donor_loss	1.0000
18:32687153:A:AT	donor_loss	1.0000
18:32687154:C:CT	donor_loss	1.0000
18:32687232:TCCTG:T	acceptor_loss	1.0000
18:32687233:CCTGT:C	acceptor_loss	1.0000
18:32687234:C:CC	acceptor_gain	1.0000
18:32687235:T:C	acceptor_loss	1.0000
18:32741926:A:AC	donor_gain	1.0000
18:32741927:C:CC	donor_gain	1.0000
18:32742057:C:CT	acceptor_gain	1.0000

AlphaMissense

4103 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:32677189:C:T	G577D	1.000
18:32677192:C:T	G576E	1.000
18:32677272:C:A	W549C	1.000
18:32677272:C:G	W549C	1.000
18:32677274:A:G	W549R	1.000
18:32677274:A:T	W549R	1.000
18:32680183:C:A	G525V	1.000
18:32680183:C:T	G525E	1.000
18:32680186:C:T	G524E	1.000
18:32680235:G:T	R508S	1.000
18:32680265:A:G	W498R	1.000
18:32680265:A:T	W498R	1.000
18:32680327:C:T	G477E	1.000
18:32680409:C:A	G477W	1.000
18:32680485:C:A	W451C	1.000
18:32680485:C:G	W451C	1.000
18:32680487:A:G	W451R	1.000
18:32680487:A:T	W451R	1.000
18:32680546:C:T	G431E	1.000
18:32680596:T:A	R414S	1.000
18:32680596:T:G	R414S	1.000
18:32687183:A:G	W404R	1.000
18:32687183:A:T	W404R	1.000
18:32687204:A:C	Y397D	1.000
18:32687206:C:G	R396P	1.000
18:32695486:C:T	G379E	1.000
18:32741943:A:G	W352R	1.000
18:32741943:A:T	W352R	1.000
18:32742011:C:T	G329E	1.000
18:32742014:C:T	G328E	1.000

dbSNP variants (sampled 300 via entrez): RS1000001090 (18:32749273 C>A,T), RS1000001745 (18:32736055 T>C), RS1000020346 (18:32691569 C>A,G,T), RS1000032593 (18:32766225 T>C), RS1000056573 (18:32749815 C>T), RS1000057735 (18:32742804 CAA>C), RS1000192231 (18:32763171 A>T), RS1000255492 (18:32722227 A>G), RS1000262670 (18:32769043 T>C), RS1000338977 (18:32736145 T>C), RS1000345560 (18:32756972 G>A,T), RS1000366085 (18:32749512 A>G,T), RS1000395942 (18:32683638 C>A,T), RS1000416502 (18:32728603 A>G), RS1000416615 (18:32711580 A>G)

Disease associations

OMIM: gene MIM:613772 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196125 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	5
Benzo(a)pyrene	affects methylation, decreases expression	4
trichostatin A	increases expression, affects cotreatment, decreases expression	3
methylmercuric chloride	decreases expression	2
entinostat	increases expression, affects cotreatment	2
Arsenic Trioxide	affects binding, decreases reaction, decreases expression	2
Ethinyl Estradiol	affects expression	2
Tetrachlorodibenzodioxin	decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Leflunomide	decreases expression	1
Panobinostat	increases expression	1
Azathioprine	decreases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression	1
Demecolcine	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6094276	Binding	Binding affinity to KLHL14 (unknown origin) at 10 uM by thermal shift assay	Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors. — J Med Chem

Clinical trials (associated diseases)

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