KLHL6

Summary

KLHL6 (kelch like family member 6, HGNC:18653) is a protein-coding gene on chromosome 3q27.1, encoding Kelch-like protein 6 (Q8WZ60). Involved in B-lymphocyte antigen receptor signaling and germinal center formation.

This gene encodes a member of the kelch-like (KLHL) family of proteins, which is involved in B-lymphocyte antigen receptor signaling and germinal-center B-cell maturation. The encoded protein contains an N-terminal broad-complex, tramtrack and bric a brac (BTB) domain that facilitates protein binding and dimerization, a BTB and C-terminal kelch (BACK) domain, and six C-terminal kelch repeat domains. Naturally occurring mutations in this gene are associated with chronic lymphocytic leukemia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 89857 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 82 total
• Druggable target: yes
• MANE Select transcript: NM_130446

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18653
Approved symbol	KLHL6
Name	kelch like family member 6
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ00029
Ensembl gene	ENSG00000172578
Ensembl biotype	protein_coding
OMIM	614214
Entrez	89857

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 1 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000341319, ENST00000468734, ENST00000487643, ENST00000489245

RefSeq mRNA: 1 — MANE Select: NM_130446 NM_130446

CCDS: CCDS3245

Canonical transcript exons

ENST00000341319 — 7 exons

Exon	Start	End
ENSE00001205218	183492494	183492707
ENSE00001205220	183494079	183494281
ENSE00001205222	183499590	183499827
ENSE00001366379	183487551	183492228
ENSE00001512473	183555361	183555706
ENSE00003490853	183527845	183528010
ENSE00003604651	183508059	183508508

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 94.24.

FANTOM5 (CAGE): breadth broad, TPM avg 10.7721 / max 252.6239, expressed in 582 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45835	6.3922	530
45834	4.0231	497
45833	0.3567	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	94.24	gold quality
bronchial epithelial cell	CL:0002328	92.64	gold quality
bronchus	UBERON:0002185	91.89	gold quality
ileal mucosa	UBERON:0000331	90.64	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.32	gold quality
lymph node	UBERON:0000029	90.19	gold quality
thymus	UBERON:0002370	89.80	gold quality
vermiform appendix	UBERON:0001154	89.38	gold quality
bone marrow cell	CL:0002092	88.23	gold quality
monocyte	CL:0000576	86.86	gold quality
leukocyte	CL:0000738	86.65	gold quality
right uterine tube	UBERON:0001302	86.05	gold quality
blood	UBERON:0000178	85.34	gold quality
caecum	UBERON:0001153	84.91	gold quality
tonsil	UBERON:0002372	84.00	gold quality
spleen	UBERON:0002106	83.45	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.34	gold quality
bone marrow	UBERON:0002371	82.79	gold quality
amniotic fluid	UBERON:0000173	82.50	gold quality
superficial temporal artery	UBERON:0001614	82.31	gold quality
granulocyte	CL:0000094	82.19	gold quality
colonic epithelium	UBERON:0000397	80.08	gold quality
pylorus	UBERON:0001166	78.18	gold quality
nasal cavity mucosa	UBERON:0001826	77.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	77.39	gold quality
right lung	UBERON:0002167	76.75	gold quality
upper lobe of left lung	UBERON:0008952	76.20	gold quality
rectum	UBERON:0001052	76.13	gold quality
upper lobe of lung	UBERON:0008948	75.86	gold quality
small intestine	UBERON:0002108	75.77	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6075	no	318.79
E-MTAB-6386	no	190.44
E-MTAB-5061	no	3.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

141 targeting KLHL6, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
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-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-607	99.97	73.62	5593
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
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-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872

Literature-anchored findings (GeneRIF, showing 5)

• characterization of two genes expressed in centroblasts of human tonsils: deltex (Drosophila) homolog 1 (DTX1), which is related to the Notch pathway and a new Kelch-like protein, KLHL6 (PMID:12617994)
• report that KLHL6, which is recurrently mutated in B cell lymphomas, is an off-target of the normal somatic hypermutation process taking place in germinal center (GC) B cells leaving open whether, despite the lack of impact of Klhl6 deficiency on GC B cell expansion, mutants could contribute to the oncogenic process (PMID:28807996)
• Abnormal expression of the KLHL6 oncogene promoted gastric cancer progression in vitro and in vivo, and its expression level in tumor tissue was found to be of prognostic value. (PMID:29044464)
• KLHL6 was positive mainly in B-cell neoplasms of germinal center derivation, including 95% of follicular lymphomas (106/112) (PMID:29140403)
• Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2. (PMID:29695787)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klhl6	ENSMUSG00000043008
rattus_norvegicus	Klhl6	ENSRNOG00000001908

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), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 6 — Q8WZ60 (reviewed: Q8WZ60)

All UniProt accessions (2): Q8WZ60, A0A0C4DGF2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in B-lymphocyte antigen receptor signaling and germinal center formation.

Tissue specificity. Found in germinal center B-cells.

RefSeq proteins (1): NP_569713* (*=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
IPR029851	BTB_POZ_KLHL6	Domain

Pfam: PF00651, PF01344, PF07707, PF24681

UniProt features (15 total): repeat 6, sequence conflict 5, domain 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WZ60-F1	87.09	0.70

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 184 (showing top): MODULE_169, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CEBPB_01, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_206, GOBP_ADAPTIVE_IMMUNE_RESPONSE, KIM_GERMINAL_CENTER_T_HELPER_UP, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOBP_B_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_ADAPTIVE_IMMUNE_RESPONSE_BASED_ON_SOMATIC_RECOMBINATION_OF_IMMUNE_RECEPTORS_BUILT_FROM_IMMUNOGLOBULIN_SUPERFAMILY_DOMAINS, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX

GO Biological Process (4): germinal center formation (GO:0002467), response to bacterium (GO:0009617), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), B cell receptor signaling pathway (GO:0050853)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), Cul3-RING ubiquitin ligase complex (GO:0031463)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
anatomical structure formation involved in morphogenesis	1
response to other organism	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
antigen receptor-mediated signaling pathway	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1272 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL6	ZMYM3	Q14202	579
KLHL6	CUL3	Q13618	568
KLHL6	MCF2L2	Q86YR7	510
KLHL6	TGM7	Q96PF1	487
KLHL6	XPO1	O14980	480
KLHL6	CCR6	P51684	480
KLHL6	CCRL2	O00421	475
KLHL6	MEF2B	Q02080	452
KLHL6	CARD11	Q9BXL7	439
KLHL6	KLHDC2	Q9Y2U9	433
KLHL6	BIRC3	Q13489	430
KLHL6	IL4	P05112	410
KLHL6	GNA13	Q14344	410
KLHL6	PTPN14	Q15678	406
KLHL6	PLEKHG5	O94827	398
KLHL6	NOTCH1	P46531	398

IntAct

54 interactions, top by confidence:

A	B	Type	Score
KLHL6	NUDCD3	psi-mi:“MI:0914”(association)	0.670
NUDCD3	KLHL6	psi-mi:“MI:0915”(physical association)	0.670
PPP1R1B	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
KLHL6	PPP1R1B	psi-mi:“MI:0915”(physical association)	0.560
SBDS	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
BYSL	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
CRY2	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
TMPO	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
FH	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
PRKN	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
SMAD4	KLHL6	psi-mi:“MI:0915”(physical association)	0.550
KLHL6	AKT1	psi-mi:“MI:0915”(physical association)	0.550
SMAD4	KLHL6	psi-mi:“MI:2364”(proximity)	0.550
KLHL6	AKT1	psi-mi:“MI:2364”(proximity)	0.550
KLHL6	SMAD4	psi-mi:“MI:0915”(physical association)	0.550
KLHL6	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
KLHL6	NUDC	psi-mi:“MI:0915”(physical association)	0.400
KLHL6	ELF1	psi-mi:“MI:0914”(association)	0.350
KLHL6	BRAF	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	KLHL6	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (233): KLHL6 (Two-hybrid), KLHL7 (Affinity Capture-MS), RC3H2 (Affinity Capture-MS), NUDCD3 (Affinity Capture-MS), DHRS4 (Affinity Capture-MS), CUL3 (Affinity Capture-Western), CUL3 (Co-localization), LAMTOR5 (Co-localization), KLHL6 (PCA), KLHL6 (Two-hybrid), CUL3 (Affinity Capture-MS), CUL3 (Affinity Capture-Western), KLHL6 (Biochemical Activity), RC3H2 (Affinity Capture-MS), RC3H2 (Affinity Capture-Western)

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: A0A1B8YAB1, A1YPR0, B0WWP2, B1H285, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, C9JR72, D3Z8N4, E0CZ16, G3X9X1, O15062, O88939, O93567, O95365, P28575, P41182, P41183, Q08CL3, Q08DK3, Q13105, Q16RL8, Q2M0J9, Q3UQV5, Q52KB5, Q5EXX3, Q5R7B8, Q5RDY3, Q5TC79, Q5ZI33, Q5ZKD9, Q5ZM39, Q60821

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KLHL6	“down-regulates quantity by destabilization”	CDK2	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4100 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:183492099:C:A	G565V	1.000
3:183492099:C:T	G565E	1.000
3:183492100:C:G	G565R	1.000
3:183492100:C:T	G565R	1.000
3:183492102:C:A	G564V	1.000
3:183492102:C:T	G564D	1.000
3:183492572:A:G	W496R	1.000
3:183492572:A:T	W496R	1.000
3:183492634:C:T	G475E	1.000
3:183492637:C:T	G474E	1.000
3:183492638:C:A	G474W	1.000
3:183494087:A:G	W448R	1.000
3:183494087:A:T	W448R	1.000
3:183494142:A:C	F429L	1.000
3:183494142:A:T	F429L	1.000
3:183494144:A:G	F429L	1.000
3:183494146:C:A	G428V	1.000
3:183494146:C:T	G428D	1.000
3:183494147:C:G	G428R	1.000
3:183494149:C:A	G427V	1.000
3:183494149:C:T	G427E	1.000
3:183494190:C:A	R413S	1.000
3:183494190:C:G	R413S	1.000
3:183494191:C:A	R413M	1.000
3:183494191:C:G	R413T	1.000
3:183494197:C:G	R411P	1.000
3:183494198:G:T	R411S	1.000
3:183494226:C:A	W401C	1.000
3:183494226:C:G	W401C	1.000
3:183494227:C:G	W401S	1.000

dbSNP variants (sampled 300 via entrez): RS1000046735 (3:183528450 G>A), RS1000196555 (3:183506076 G>A), RS1000205313 (3:183544007 T>C), RS1000230775 (3:183504542 T>C), RS1000238198 (3:183544470 T>C), RS1000246774 (3:183515948 T>A), RS1000248480 (3:183532278 G>A), RS1000330986 (3:183550670 C>T), RS1000336731 (3:183488988 T>A,C), RS1000396312 (3:183510740 G>A), RS1000415485 (3:183516312 T>C), RS1000442210 (3:183549489 T>C), RS1000473370 (3:183549646 C>T), RS1000581280 (3:183542875 G>C,T), RS1000619459 (3:183553415 C>G)

Disease associations

OMIM: gene MIM:614214 | 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): CHEMBL6066409 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.38	Kd	42.03	nM	CHEMBL3752910
7.25	ED50	56.74	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149877: Binding affinity to human KLHL6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0420	uM

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Nickel	increases expression	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
terbufos	decreases methylation	1
coumarin	increases phosphorylation	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Diuron	decreases expression	1
Fonofos	decreases methylation	1
Formaldehyde	decreases expression	1
Parathion	decreases methylation	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Mifepristone	increases expression	1
Antirheumatic Agents	decreases 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
CHEMBL5652919	Binding	Binding affinity to human KLHL6 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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