KLHL10

Summary

KLHL10 (kelch like family member 10, HGNC:18829) is a protein-coding gene on chromosome 17q21.2, encoding Kelch-like protein 10 (Q6JEL2). May be a substrate-specific adapter of a CUL3-based E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins during spermatogenesis.

The protein encoded by this gene belongs to the kelch repeat-containing family, and contains an N-terminal BTB/POZ domain a BACK domain and six C-terminal kelch repeats. Kelch domains are thought to form a four stranded beta-sheet blade structure that can fold into a beta-propeller domain when multiple kelch repeats are found together. Mutations in this gene have been associated with oligozoospermia in some infertile males.

Source: NCBI Gene 317719 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spermatogenic failure 11 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 85 total — 1 pathogenic
• Phenotypes (HPO): 12
• MANE Select transcript: NM_152467

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18829
Approved symbol	KLHL10
Name	kelch like family member 10
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32662
Ensembl gene	ENSG00000161594
Ensembl biotype	protein_coding
OMIM	608778
Entrez	317719

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000293303, ENST00000438813, ENST00000448203, ENST00000485613, ENST00000859834, ENST00000913027, ENST00000959872

RefSeq mRNA: 3 — MANE Select: NM_152467 NM_001329595, NM_001329596, NM_152467

CCDS: CCDS42340

Canonical transcript exons

ENST00000293303 — 5 exons

Exon	Start	End
ENSE00001058936	41847933	41848384
ENSE00001118398	41837825	41838126
ENSE00002352917	41847261	41847410
ENSE00002367136	41845126	41845743
ENSE00002398704	41841823	41842312

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 99.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0383 / max 35.1846, expressed in 3 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160884	0.0297	3
160885	0.0059	3
208195	0.0027	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.54	gold quality
left testis	UBERON:0004533	93.58	gold quality
right testis	UBERON:0004534	93.46	gold quality
testis	UBERON:0000473	90.96	gold quality
adult organism	UBERON:0007023	86.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.56	silver quality
buccal mucosa cell	CL:0002336	74.79	silver quality
lower esophagus muscularis layer	UBERON:0035833	65.75	gold quality
lower esophagus	UBERON:0013473	65.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	63.59	gold quality
right coronary artery	UBERON:0001625	62.95	gold quality
popliteal artery	UBERON:0002250	62.56	gold quality
tibial artery	UBERON:0007610	62.55	gold quality
mucosa of stomach	UBERON:0001199	60.55	gold quality
cerebellar vermis	UBERON:0004720	60.27	gold quality
left coronary artery	UBERON:0001626	59.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	59.10	gold quality
aorta	UBERON:0000947	58.98	gold quality
coronary artery	UBERON:0001621	58.96	gold quality
smooth muscle tissue	UBERON:0001135	58.59	gold quality
myocardium	UBERON:0002349	55.95	gold quality
descending thoracic aorta	UBERON:0002345	55.90	gold quality
thoracic aorta	UBERON:0001515	54.47	gold quality
esophagus	UBERON:0001043	54.39	gold quality
ascending aorta	UBERON:0001496	54.07	gold quality
body of uterus	UBERON:0009853	53.32	gold quality
lower esophagus mucosa	UBERON:0035834	51.85	gold quality
left uterine tube	UBERON:0001303	51.42	gold quality
myometrium	UBERON:0001296	51.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.28

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• The KLHL-10 gene is not a major contributor to azoospermia, oligospermia or asthenospermia in Chinese population. (PMID:20218307)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl10a	ENSDARG00000005814
danio_rerio	klhl10b.2	ENSDARG00000112170
danio_rerio	klhl10b.1	ENSDARG00000115489
mus_musculus	Klhl10	ENSMUSG00000001558
rattus_norvegicus	Klhl10	ENSRNOG00000016749
drosophila_melanogaster		FBGN0040038
caenorhabditis_elegans		WBGENE00002186
caenorhabditis_elegans		WBGENE00018563

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), 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), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 10 — Q6JEL2 (reviewed: Q6JEL2)

All UniProt accessions (4): A0A140VJM8, C9J999, C9JHB3, Q6JEL2

UniProt curated annotations — full annotation on UniProt →

Function. May be a substrate-specific adapter of a CUL3-based E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins during spermatogenesis.

Subunit / interactions. Self-associates. Interacts with CUL3; indicative for the participation in an E3 ubiquitin ligase complex.

Subcellular location. Cytoplasm.

Disease relevance. Spermatogenic failure 11 (SPGF11) [MIM:615081] An infertility disorder caused by spermatogenesis defects. It results in decreased sperm motility, concentration, and multiple sperm structural defects. Oligozoospermia is usually observed in SPGF11 patients. In addition to oligozoospermia, teratozoospermia and moderate asthenozoospermia is observed in some cases. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (3): NP_001316524, NP_001316525, NP_689680* (*=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
IPR030608	KLHL10_BTB/POZ	Domain

Pfam: PF00651, PF01344, PF07707

UniProt features (12 total): repeat 6, sequence variant 2, chain 1, domain 1, sequence conflict 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6JEL2-F1	91.89	0.87

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 (1): 501

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 101 (showing top): AAGCAAT_MIR137, TGCGCANK_UNKNOWN, GOBP_MALE_GENITALIA_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_MALE_GAMETE_GENERATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_SEX_DIFFERENTIATION, WEBER_METHYLATED_LCP_IN_SPERM_UP, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_HOMEOSTASIS_OF_NUMBER_OF_CELLS_WITHIN_A_TISSUE, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION

GO Biological Process (10): cell morphogenesis (GO:0000902), spermatid development (GO:0007286), male gonad development (GO:0008584), fertilization (GO:0009566), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), male genitalia morphogenesis (GO:0048808), homeostasis of number of cells within a tissue (GO:0048873), spermatogenesis (GO:0007283), cell differentiation (GO:0030154)

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
anatomical structure morphogenesis	1
germ cell development	1
spermatid differentiation	1
gonad development	1
development of primary male sexual characteristics	1
sexual reproduction	1
reproductive process	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
male genitalia development	1
genitalia morphogenesis	1
male anatomical structure morphogenesis	1
tissue homeostasis	1
homeostasis of number of cells	1
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	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

1000 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL10	PRM2	P04554	856
KLHL10	PRM1	P04553	846
KLHL10	CUL3	Q13618	736
KLHL10	IQCF1	Q8N6M8	664
KLHL10	SPATA16	Q9BXB7	596
KLHL10	TSSK4	Q6SA08	520
KLHL10	TSSK3	Q96PN8	514
KLHL10	TEX11	Q8IYF3	477
KLHL10	CCDC83	Q8IWF9	466
KLHL10	TNP2	Q05952	444
KLHL10	FSCN3	Q9NQT6	442
KLHL10	SEPTIN12	Q8IYM1	433
KLHL10	OR6C4	Q8NGE1	432
KLHL10	SYCP3	Q8IZU3	430
KLHL10	TSSK6	Q9BXA6	430

IntAct

17 interactions, top by confidence:

A	B	Type	Score
KLHL10	GSTO2	psi-mi:“MI:0915”(physical association)	0.560
RAD51C	PTPN9	psi-mi:“MI:0914”(association)	0.530
KLHL10	PXDNL	psi-mi:“MI:0914”(association)	0.530
KLHL10	HSPA8	psi-mi:“MI:0914”(association)	0.530
KLHL10	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
KLHL10		psi-mi:“MI:0915”(physical association)	0.400
NUDCD3	KLHL10	psi-mi:“MI:0915”(physical association)	0.400
KLHL10	KLHL10	psi-mi:“MI:0915”(physical association)	0.370
Cul3	KLHL10	psi-mi:“MI:0915”(physical association)	0.370
KLHL10	BCL2L11	psi-mi:“MI:0914”(association)	0.350
KLHL10	GSTO2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (73): KLHL10 (Affinity Capture-MS), FBXL17 (Affinity Capture-MS), COPS7A (Affinity Capture-MS), COPS2 (Affinity Capture-MS), COPS7B (Affinity Capture-MS), MVK (Affinity Capture-MS), PRMT3 (Affinity Capture-MS), COPS5 (Affinity Capture-MS), COPS6 (Affinity Capture-MS), DNAJB5 (Affinity Capture-MS), C15orf39 (Affinity Capture-MS), COPS3 (Affinity Capture-MS), PSME4 (Affinity Capture-MS), GPS1 (Affinity Capture-MS), BCL2L11 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8Q1W5, A6QQY2, B0WWP2, B3NDN0, B4HIK1, B4L0G9, B4LIG6, B4PD06, D3Z8N4, E0CZ16, E1B932, E7F6F9, E9Q4F2, F1LZ52, O94889, P28575, P57790, P59280, Q08DK3, Q14145, Q16RL8, Q2T9Z7, Q53G59, Q5R774, Q5R7B8, Q5U374, Q5ZKD9, Q5ZLD3, Q684M4, Q6DFF6, Q6JEL2, Q6JEL3, Q6NRH0, Q6TDP3, Q6TDP4, Q6ZPT1, Q7QGL0, Q80TF4, Q8BZM0, Q8K430

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	53
Likely benign	5
Benign	16

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
996145	NM_152467.5(KLHL10):c.985C>T (p.Arg329Cys)	Pathogenic

SpliceAI

896 predictions. Top by Δscore:

Variant	Effect	Δscore
17:41835860:TGTA:T	donor_gain	1.0000
17:41838072:GCTT:G	donor_gain	1.0000
17:41838080:T:G	donor_gain	1.0000
17:41842226:G:GT	donor_gain	1.0000
17:41845120:TCTTA:T	acceptor_loss	1.0000
17:41845121:CTTA:C	acceptor_loss	1.0000
17:41845122:TTAGG:T	acceptor_loss	1.0000
17:41845123:TAGGT:T	acceptor_loss	1.0000
17:41845124:AGGTT:A	acceptor_loss	1.0000
17:41845125:G:A	acceptor_loss	1.0000
17:41835854:GGTA:G	donor_loss	0.9900
17:41835855:GTA:G	donor_loss	0.9900
17:41835856:TA:T	donor_loss	0.9900
17:41835857:A:AT	donor_loss	0.9900
17:41835858:C:CA	donor_loss	0.9900
17:41835858:CCTG:C	donor_gain	0.9900
17:41836168:T:TA	donor_gain	0.9900
17:41836183:T:TA	donor_gain	0.9900
17:41837989:GAAGA:G	donor_gain	0.9900
17:41837993:A:G	donor_gain	0.9900
17:41838040:C:T	donor_gain	0.9900
17:41838057:TCATC:T	donor_gain	0.9900
17:41838071:GGCTT:G	donor_gain	0.9900
17:41838075:T:TG	donor_gain	0.9900
17:41841822:GA:G	acceptor_gain	0.9900
17:41842143:TGA:T	donor_gain	0.9900
17:41842206:A:G	donor_gain	0.9900
17:41842308:CTAAG:C	donor_loss	0.9900
17:41842309:TAAG:T	donor_loss	0.9900
17:41842310:AAGG:A	donor_loss	0.9900

AlphaMissense

4089 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:41842212:T:A	L195H	1.000
17:41842256:T:A	W210R	1.000
17:41842256:T:C	W210R	1.000
17:41845129:C:A	R230S	1.000
17:41845229:T:C	L263P	1.000
17:41845300:C:A	R287S	1.000
17:41845331:G:A	G297D	1.000
17:41845333:G:C	G298R	1.000
17:41845334:G:A	G298D	1.000
17:41845334:G:T	G298V	1.000
17:41845336:T:A	W299R	1.000
17:41845336:T:C	W299R	1.000
17:41845338:G:C	W299C	1.000
17:41845338:G:T	W299C	1.000
17:41845393:T:A	W318R	1.000
17:41845393:T:C	W318R	1.000
17:41845395:G:C	W318C	1.000
17:41845395:G:T	W318C	1.000
17:41845432:T:C	Y331H	1.000
17:41845474:G:A	G345R	1.000
17:41845474:G:C	G345R	1.000
17:41845474:G:T	G345W	1.000
17:41845475:G:A	G345E	1.000
17:41845475:G:T	G345V	1.000
17:41845477:G:A	G346R	1.000
17:41845477:G:C	G346R	1.000
17:41845477:G:T	G346W	1.000
17:41845478:G:A	G346E	1.000
17:41845478:G:T	G346V	1.000
17:41845480:T:C	F347L	1.000

dbSNP variants (sampled 300 via entrez): RS1000426034 (17:41836028 C>T), RS1001077043 (17:41847014 C>T), RS1001373131 (17:41840480 C>A), RS1001552401 (17:41837003 T>A,G), RS1001725341 (17:41843585 A>G), RS1001972869 (17:41842247 A>G), RS1002963922 (17:41838275 T>C), RS1004380140 (17:41838268 A>C,T), RS1004826848 (17:41836643 C>T), RS1004884718 (17:41843532 T>G), RS1004979548 (17:41843272 G>A), RS1005338701 (17:41839632 A>G), RS1005544092 (17:41846405 C>T), RS1005974506 (17:41844750 T>C,G), RS1006054971 (17:41846179 T>G)

Disease associations

OMIM: gene MIM:608778 | disease phenotypes: MIM:615081

GenCC curated gene-disease

Disease	Classification	Inheritance
spermatogenic failure 11	Moderate	Autosomal dominant
male infertility with azoospermia or oligozoospermia due to single gene mutation	Supportive	Autosomal dominant

Mondo (2): spermatogenic failure 11 (MONDO:0014037), (MONDO:0018393)

Orphanet (0):

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000027	Azoospermia
HP:0000118	Phenotypic abnormality
HP:0000798	Oligozoospermia
HP:0000837	Increased circulating gonadotropin level
HP:0003251	Male infertility
HP:0008669	Abnormal spermatogenesis
HP:0008734	Decreased testicular size
HP:0011961	Non-obstructive azoospermia
HP:0011962	Obstructive azoospermia
HP:0012207	Reduced sperm motility
HP:0012864	Abnormal sperm morphology

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004619_44	Reticulocyte fraction of red cells	6.000000e-13
GCST004622_53	Reticulocyte count	1.000000e-14
GCST90002385_414	High light scatter reticulocyte count	2.000000e-38
GCST90002387_31	Immature fraction of reticulocytes	2.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
tobacco tar	decreases reaction, increases expression	1
diallyl disulfide	decreases reaction, increases expression	1
allyl sulfide	decreases reaction, increases expression	1
bisphenol S	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Indomethacin	increases expression, affects cotreatment	1
Methotrexate	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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