KLHDC1

Summary

KLHDC1 (kelch domain containing 1, HGNC:19836) is a protein-coding gene on chromosome 14q21.3, encoding Kelch domain-containing protein 1 (Q8N7A1). Substrate-recognition component of a Cul5-RING (CRL5) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation.

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Is active in Cul5-RING ubiquitin ligase complex and cytosol.

Source: NCBI Gene 122773 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 71 total
• MANE Select transcript: NM_172193

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19836
Approved symbol	KLHDC1
Name	kelch domain containing 1
Location	14q21.3
Locus type	gene with protein product
Status	Approved
Aliases	MST025
Ensembl gene	ENSG00000197776
Ensembl biotype	protein_coding
OMIM	611281
Entrez	122773

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000359332, ENST00000553274, ENST00000554512, ENST00000555704, ENST00000556392, ENST00000557128, ENST00000905326, ENST00000905327, ENST00000905328, ENST00000905329, ENST00000971499, ENST00000971500, ENST00000971501, ENST00000971502

RefSeq mRNA: 1 — MANE Select: NM_172193 NM_172193

CCDS: CCDS9692

Canonical transcript exons

ENST00000359332 — 13 exons

Exon	Start	End
ENSE00001406365	49751586	49753150
ENSE00002469203	49693120	49693290
ENSE00003479596	49728926	49729009
ENSE00003490469	49723874	49723952
ENSE00003501282	49732704	49732816
ENSE00003511209	49729490	49729548
ENSE00003516328	49734589	49734661
ENSE00003529977	49740098	49740182
ENSE00003546435	49709159	49709229
ENSE00003565401	49725686	49725769
ENSE00003577943	49709709	49709826
ENSE00003595820	49743753	49743805
ENSE00003710913	49710263	49710381

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 93.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.6335 / max 162.8225, expressed in 1181 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139440	2.4041	990
139441	1.2294	486

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	93.29	gold quality
tibia	UBERON:0000979	91.74	gold quality
deltoid	UBERON:0001476	89.23	gold quality
vastus lateralis	UBERON:0001379	88.33	gold quality
corpus callosum	UBERON:0002336	88.27	gold quality
quadriceps femoris	UBERON:0001377	87.63	gold quality
biceps brachii	UBERON:0001507	87.37	gold quality
germinal epithelium of ovary	UBERON:0001304	87.17	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	84.73	gold quality
left ovary	UBERON:0002119	84.58	gold quality
caput epididymis	UBERON:0004358	84.16	gold quality
parietal pleura	UBERON:0002400	84.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	83.88	gold quality
right ovary	UBERON:0002118	83.07	gold quality
skeletal muscle tissue	UBERON:0001134	83.05	gold quality
superficial temporal artery	UBERON:0001614	82.75	gold quality
mucosa of stomach	UBERON:0001199	82.69	gold quality
seminal vesicle	UBERON:0000998	82.53	gold quality
primary visual cortex	UBERON:0002436	82.44	gold quality
ovary	UBERON:0000992	82.39	gold quality
corpus epididymis	UBERON:0004359	82.25	gold quality
tendon	UBERON:0000043	82.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.97	gold quality
tibial nerve	UBERON:0001323	81.92	gold quality
muscle tissue	UBERON:0002385	81.79	gold quality
Brodmann (1909) area 46	UBERON:0006483	81.73	gold quality
mucosa of paranasal sinus	UBERON:0005030	81.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.58	gold quality
cauda epididymis	UBERON:0004360	81.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.06	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

91 targeting KLHDC1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-205-3P	99.92	69.92	3165

Literature-anchored findings (GeneRIF, showing 3)

• Data show that KLHDC1 and KLHDC2 have differential localization and activity in cultured mammalian cells. (PMID:16964437)
• Blocking CCR4 and CCR10 simultaneously, or their ligands, should be beneficial in the treatment of T-cell-mediated skin diseases. (PMID:18095942)
• The crystal structures of the apo form of the mutated Keap1 Kelch domain (1.98 A resolution) and of the complex with an Nrf2-derived peptide obtained by soaking (2.20 A resolution) are reported. (PMID:23722832)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klhdc1	ENSMUSG00000051890
rattus_norvegicus	Klhdc1	ENSRNOG00000004425
drosophila_melanogaster	Hcf	FBGN0039904
caenorhabditis_elegans		WBGENE00001827

Paralogs (10): FBXO42 (ENSG00000037637), LZTR1 (ENSG00000099949), KLHDC4 (ENSG00000104731), HCFC2 (ENSG00000111727), KLHDC3 (ENSG00000124702), KLHDC10 (ENSG00000128607), RABEPK (ENSG00000136933), KLHDC9 (ENSG00000162755), KLHDC2 (ENSG00000165516), HCFC1 (ENSG00000172534)

Protein

Protein identifiers

Kelch domain-containing protein 1 — Q8N7A1 (reviewed: Q8N7A1)

All UniProt accessions (5): Q8N7A1, G3V2D3, G3V3T1, G3V4I4, G3V5V5

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of a Cul5-RING (CRL5) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL5(KLHDC1) complex mediates ubiquitination and degradation of truncated SELENOS selenoprotein produced by failed UGA/Sec decoding, which ends with a glycine.

Subunit / interactions. Component of a CRL5 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL5, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC1.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed, with high levels in skeletal muscle, pancreas and liver. Undetectable in peripheral blood leukocytes.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_751943* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily

Pfam: PF24681

UniProt features (8 total): repeat 6, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N7A1-F1	93.74	0.86

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 136 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_UP, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX, GOCC_UBIQUITIN_LIGASE_COMPLEX, TST1_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_DN, WANG_RESPONSE_TO_GSK3_INHIBITOR_SB216763_UP, WIERENGA_STAT5A_TARGETS_DN

GO Biological Process (2): protein ubiquitination (GO:0016567), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627)

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

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), Cul5-RING ubiquitin ligase complex (GO:0031466), cullin-RING ubiquitin ligase complex (GO:0031461)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein modification by small protein conjugation	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
cullin-RING ubiquitin ligase complex	1
ubiquitin ligase complex	1

Protein interactions and networks

STRING

824 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHDC1	CREB3	O43889	852
KLHDC1	KBTBD13	C9JR72	531
KLHDC1	KLHL40	Q2TBA0	520
KLHDC1	CTDSPL2	Q05D32	502
KLHDC1	GAS2L1	Q99501	496
KLHDC1	ASB14	A6NK59	477
KLHDC1	KLHL41	O60662	475
KLHDC1	KLHL20	Q9Y2M5	469
KLHDC1	KLHL31	Q9H511	466
KLHDC1	NAE1	Q13564	438
KLHDC1	AGGF1	Q8N302	427
KLHDC1	IPP	Q9Y573	404
KLHDC1	KLHL11	Q9NVR0	389
KLHDC1	EFHC1	Q5JVL4	372
KLHDC1	STAU2	Q9NUL3	363

IntAct

3 interactions, top by confidence:

A	B	Type	Score
KLHDC1	NUDCD3	psi-mi:“MI:0915”(physical association)	0.400
KLHDC1	NUDC	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (4): KLHDC1 (Affinity Capture-MS), KLHDC1 (Affinity Capture-MS), KLHDC1 (Positive Genetic), KLHDC1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A2R8Q1W5, A2AAX3, A4IF63, A6QQY2, D3ZA50, D3ZQG6, F7H9X2, G3X9X1, O95199, P28575, P57790, Q14145, Q28DE7, Q2T9Z7, Q2WGJ6, Q56A24, Q58CV6, Q59H18, Q5BK60, Q5GIG6, Q5R774, Q5RCZ7, Q5RDY3, Q5U3Y0, Q5U580, Q5ZJU2, Q5ZLD3, Q684M4, Q6AYI2, Q6P798, Q6TFL4, Q6ZPT1, Q7TQP6, Q80TF4, Q80YG3, Q8BRG6, Q8BSF5, Q8IY47, Q8N7A1, Q8VEM9

Diamond homologs: A1XLE2, G1FNI6, O04316, O04318, O49326, Q4V8F4, Q5EA50, Q5ZJ37, Q6GQN7, Q7Z6M1, Q80YG3, Q8N7A1, Q8RY71, Q93XW5, Q9SDM9, A1AJH6, A1JMV0, A4TK48, A5F7B3, A5UB03, A5UFV3, A5VU94, A7FJ01, A7ZVK8, A8A834, A9MH34, A9N6P2, A9WYA0, B4T2W1, B4TSP0, B5R066, P39371, P44544, Q0SXL5, Q0T900, Q1C8L8, Q1CHD7, Q1R2K5, Q2YK69, Q31T32

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2463 predictions. Top by Δscore:

Variant	Effect	Δscore
14:49693280:GGGGC:G	donor_gain	1.0000
14:49693281:GGGC:G	donor_gain	1.0000
14:49707934:GAA:G	donor_gain	1.0000
14:49707992:C:G	donor_gain	1.0000
14:49709157:A:AG	acceptor_gain	1.0000
14:49709158:G:GC	acceptor_gain	1.0000
14:49709158:GTCT:G	acceptor_gain	1.0000
14:49709227:GTG:G	donor_gain	1.0000
14:49709230:G:GG	donor_gain	1.0000
14:49709813:GA:G	donor_gain	1.0000
14:49709825:GA:G	donor_gain	1.0000
14:49709827:G:GG	donor_gain	1.0000
14:49710281:C:CA	acceptor_gain	1.0000
14:49723873:GACTA:G	acceptor_gain	1.0000
14:49725680:TTTTA:T	acceptor_loss	1.0000
14:49725683:TAG:T	acceptor_loss	1.0000
14:49725685:GGAA:G	acceptor_gain	1.0000
14:49725765:TTAAA:T	donor_gain	1.0000
14:49725767:AAAG:A	donor_loss	1.0000
14:49725770:G:GG	donor_gain	1.0000
14:49725770:G:T	donor_loss	1.0000
14:49725771:T:G	donor_loss	1.0000
14:49728924:AG:A	acceptor_gain	1.0000
14:49728925:GG:G	acceptor_gain	1.0000
14:49729488:A:AG	acceptor_gain	1.0000
14:49729489:G:GG	acceptor_gain	1.0000
14:49729489:GC:G	acceptor_gain	1.0000
14:49729489:GCA:G	acceptor_gain	1.0000
14:49729489:GCAA:G	acceptor_gain	1.0000
14:49729489:GCAAA:G	acceptor_gain	1.0000

AlphaMissense

2696 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:49693276:T:A	W28R	0.999
14:49693276:T:C	W28R	0.999
14:49693279:G:T	G29W	0.999
14:49693280:G:A	G29E	0.999
14:49693282:G:C	G30R	0.999
14:49693283:G:A	G30D	0.999
14:49693283:G:T	G30V	0.999
14:49709795:G:A	G85E	0.999
14:49709798:G:A	G86E	0.999
14:49710305:T:A	W110R	0.999
14:49710305:T:C	W110R	0.999
14:49710348:G:C	R124P	0.999
14:49710354:A:T	K126I	0.999
14:49723888:G:A	G140D	0.999
14:49723888:G:T	G140V	0.999
14:49723891:G:A	G141D	0.999
14:49723891:G:T	G141V	0.999
14:49723896:G:T	G143W	0.999
14:49723897:G:A	G143E	0.999
14:49725705:G:A	G168E	0.999
14:49725707:T:A	W169R	0.999
14:49725707:T:C	W169R	0.999
14:49725709:G:C	W169C	0.999
14:49725709:G:T	W169C	0.999
14:49725749:T:A	W183R	0.999
14:49725749:T:C	W183R	0.999
14:49728996:G:A	G213D	0.999
14:49728999:G:A	G214E	0.999
14:49729538:T:A	W234R	0.999
14:49729538:T:C	W234R	0.999

dbSNP variants (sampled 300 via entrez): RS1000023923 (14:49730877 C>T), RS1000059170 (14:49738247 G>A), RS1000107770 (14:49747604 G>T), RS1000118199 (14:49731108 C>T), RS1000127167 (14:49722271 C>T), RS1000138266 (14:49691736 T>C), RS1000186320 (14:49699019 C>A), RS1000214624 (14:49691978 G>A), RS1000252209 (14:49731898 G>C), RS1000355275 (14:49725069 C>A), RS1000366257 (14:49737998 A>G), RS1000381587 (14:49707450 C>T), RS1000457596 (14:49719075 C>T), RS1000553269 (14:49712158 T>G), RS1000622847 (14:49713470 A>C,G,T)

Disease associations

OMIM: gene MIM:611281 | 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
GCST003652_3	Parkinson’s disease (familial, age at onset)	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
Nickel	decreases expression	2
bisphenol F	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Arsenic	affects methylation	1
Cadmium	decreases expression	1
Clorgyline	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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