KLHL3

Summary

KLHL3 (kelch like family member 3, HGNC:6354) is a protein-coding gene on chromosome 5q31.2, encoding Kelch-like protein 3 (Q9UH77). Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron.

This gene is ubiquitously expressed and encodes a full-length protein which has an N-terminal BTB domain followed by a BACK domain and six kelch-like repeats in the C-terminus. These kelch-like repeats promote substrate ubiquitination of bound proteins via interaction of the BTB domain with the CUL3 (cullin 3) component of a cullin-RING E3 ubiquitin ligase (CRL) complex. Muatations in this gene cause pseudohypoaldosteronism type IID (PHA2D); a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 26249 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pseudohypoaldosteronism type 2D (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 409 total — 19 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 8
• Druggable target: yes
• MANE Select transcript: NM_017415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6354
Approved symbol	KLHL3
Name	kelch like family member 3
Location	5q31.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1129
Ensembl gene	ENSG00000146021
Ensembl biotype	protein_coding
OMIM	605775
Entrez	26249

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding, 7 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000309755, ENST00000447439, ENST00000502381, ENST00000504208, ENST00000504496, ENST00000505853, ENST00000506491, ENST00000506873, ENST00000508657, ENST00000509694, ENST00000510529, ENST00000512977, ENST00000514149, ENST00000515334, ENST00000896230, ENST00000896231, ENST00000896232, ENST00000941327

RefSeq mRNA: 3 — MANE Select: NM_017415 NM_001257194, NM_001257195, NM_017415

CCDS: CCDS4192, CCDS58969, CCDS58970

Canonical transcript exons

ENST00000309755 — 15 exons

Exon	Start	End
ENSE00001415249	137735633	137736089
ENSE00001520048	137617500	137622126
ENSE00003482750	137709750	137709856
ENSE00003502623	137720465	137720584
ENSE00003518233	137661915	137662031
ENSE00003528134	137658131	137658280
ENSE00003553149	137677545	137677654
ENSE00003571116	137698287	137698408
ENSE00003602065	137625753	137625896
ENSE00003613923	137639860	137639977
ENSE00003624022	137634037	137634165
ENSE00003628470	137638953	137639150
ENSE00003631622	137628297	137628437
ENSE00003650389	137692285	137692447
ENSE00003785063	137637294	137637395

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 97.52.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9687 / max 278.9765, expressed in 670 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63641	1.1226	431
63638	0.9114	316
63642	0.3586	151
63640	0.2947	186
63639	0.2286	104
63643	0.0287	6
63644	0.0154	5
63637	0.0088	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	97.52	gold quality
middle temporal gyrus	UBERON:0002771	94.11	gold quality
cerebellum	UBERON:0002037	94.04	gold quality
cerebellar cortex	UBERON:0002129	93.80	gold quality
cerebellar hemisphere	UBERON:0002245	93.74	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.62	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.79	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.52	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.10	gold quality
sural nerve	UBERON:0015488	89.74	gold quality
CA1 field of hippocampus	UBERON:0003881	89.57	gold quality
inferior olivary complex	UBERON:0002127	89.49	gold quality
postcentral gyrus	UBERON:0002581	88.87	gold quality
myocardium	UBERON:0002349	88.39	gold quality
pigmented layer of retina	UBERON:0001782	88.01	gold quality
retina	UBERON:0000966	87.99	gold quality
cardiac atrium	UBERON:0002081	87.43	gold quality
parietal lobe	UBERON:0001872	87.28	gold quality
primary visual cortex	UBERON:0002436	87.13	gold quality
right atrium auricular region	UBERON:0006631	87.10	gold quality
superior frontal gyrus	UBERON:0002661	86.98	gold quality
entorhinal cortex	UBERON:0002728	86.61	gold quality
lateral globus pallidus	UBERON:0002476	86.52	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	86.31	gold quality
tibia	UBERON:0000979	86.08	gold quality
apex of heart	UBERON:0002098	85.80	gold quality
endothelial cell	CL:0000115	85.26	gold quality
heart left ventricle	UBERON:0002084	84.87	gold quality
occipital lobe	UBERON:0002021	84.84	gold quality
cardiac ventricle	UBERON:0002082	84.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1001.03
E-CURD-119	yes	946.60
E-ANND-3	yes	6.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

189 targeting KLHL3, 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-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-9-5P	100.00	72.28	2361
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-4789-3P	99.99	70.75	2484
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515

Literature-anchored findings (GeneRIF, showing 22)

• fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis (PMID:22266938)
• identified KLHL3 as a third gene responsible for familial hyperkalemic hypertension; study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure (PMID:22406640)
• The CUL3-KLHL3 E3 ligase complex mutated in Gordon’s hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. (PMID:23387299)
• Disease causing mutations in human KLHL3 disrupt the interaction with CUL3, a crystallographic study. (PMID:23573258)
• CUL3 and KLHL3 have roles in in electrolyte homeostasis and in Pseudohypoaldosteronism type II (PMID:23576762)
• KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex (PMID:23665031)
• analysis of how mutations of KLHL3 show less ability to ubiquitinate WNK4 because of KLHL3’s low stability and/or decreased binding to CUL3 or WNK4 (PMID:23962426)
• CUL3 and KLHL3 gene products are physiologically important regulators of thiazide-sensitive distal nephron sodium chloride reabsorption. (PMID:24266877)
• Hyperkalemic hypertension-associated cul3 mutations depletes KLHL3, preventing WNK degradation, despite increased CUL3-mediated WNK ubiquitylation. (PMID:25250572)
• KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. (PMID:25313067)
• Familial hyperkalemia and hypertension caused by KLHL3 mutations is accompanied by hypercalciuria as well as hyperkalemia and hypertension. (PMID:25925082)
• Data indicate that WNK lysine deficient protein kinase 4 protein (WNK4) was degraded not only by proteasomes but also by atypical protein kinase C scaffold protein p62 (p62)-kelch-like 3 protein (KLHL3)-mediated selective autophagy. (PMID:26349538)
• Akt and PKA phosphorylated KLHL3 at S433, and phosphorylation of KLHL3 by PKA inhibited WNK4 degradation. (PMID:26435498)
• This study provides substantial new insights into the role of phosphorylation of KLHL3 in regulating the interaction with WNK4 (PMID:27727489)
• Mutation in the KLHL3 gene is associated with Gordon syndrome. (PMID:28222034)
• The results demonstrate that Hcy decreases the expression of cMyBP-C through a KLHL3-mediated ubiquitin-proteasome pathway, and thereby influences heart development. (PMID:28315668)
• A new recessive mutation in KLHL3 (S553L) was identified in familial hyperkalemia and hypertension. Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form. (PMID:28511177)
• tacrolimus increases levels of KLHL3(S433-P), resulting in increased levels of WNK4, phosphorylated SPAK, and Na-Cl cotransporter.These findings demonstrate that KLHL3(S433-P) is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies. (PMID:30718414)
• Molecular dynamics simulations indicate the effects of these mutations on the interaction between the Kelch domain of kelch-like protein 3 (KLHL3) and the acidic motif (AM) of WNK lysine deficient protein kinase 4 protein (WNK4). (PMID:30931564)
• The KLHL3 rs7444370 variant could be a protective factor in the pathogenesis of females’ essential hypertension (PMID:31096542)
• Kelch-like protein 3 in human disease and therapy. (PMID:35585379)
• KLHL3-dependent WNK4 degradation affected by potassium through the neddylation and autophagy pathway. (PMID:37481568)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl3	ENSDARG00000056647
mus_musculus	Klhl3	ENSMUSG00000014164
rattus_norvegicus	Klhl3	ENSRNOG00000019533

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), 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), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 3 — Q9UH77 (reviewed: Q9UH77)

All UniProt accessions (3): D6R9K4, D6RH21, Q9UH77

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron. The BCR(KLHL3) complex acts by mediating ubiquitination and degradation of WNK1 and WNK4, two activators of Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney, thereby regulating NaCl reabsorption. The BCR(KLHL3) complex also mediates ubiquitination and degradation of WNK3. The BCR(KLHL3) complex also mediates ubiquitination of CLDN8, a tight-junction protein required for paracellular chloride transport in the kidney, leading to its degradation.

Subunit / interactions. Homodimer. Component of the BCR(KLHL3) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL3 and RBX1. Interacts with CLDN8.

Subcellular location. Cytoplasm. Cytosol. Cytoskeleton.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylation at Ser-433 by PKA or PKC decreases the interaction with WNK1 and WNK4, leading to inhibit their degradation by the BCR(KLHL3) complex. Phosphorylated at Ser-433 by PKC in response to angiotensin II signaling, decreasing ability to promote degradation of WNK1 and WNK4, leading to activation of Na-Cl cotransporter SLC12A3/NCC. Phosphorylation at Ser-433 is increased by insulin. Dephosphorylated at Ser-433 by calcineurin PPP3CA, promoting degradation of WNK1 and WNK4.

Disease relevance. Pseudohypoaldosteronism 2D (PHA2D) [MIM:614495] A disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. PHA2D inheritance is autosomal dominant or recessive. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the KLHL3 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UH77-1	A, KLHL3A	yes
Q9UH77-2	B, KLHL3B
Q9UH77-3	C, KLHL3C

RefSeq proteins (3): NP_001244123, NP_001244124, NP_059111* (*=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
IPR030578	KLHL3_BACK	Domain

Pfam: PF00651, PF01344, PF07707

UniProt features (91 total): sequence variant 36, strand 29, turn 7, repeat 6, modified residue 5, domain 2, splice variant 2, mutagenesis site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4CH9	X-RAY DIFFRACTION	1.84
5NKP	X-RAY DIFFRACTION	2.8
4HXI	X-RAY DIFFRACTION	3.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UH77-F1	90.53	0.71

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): 295, 375, 376, 433, 10

Mutagenesis-validated functional residues (2):

Position	Phenotype
433	abolished phosphorylation by pkc, promoting ubiquitination and degradation of wnk4.
433	mimics phosphorylation, preventing binding and degradation of wnk4.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 207 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GCAAGGA_MIR502, GOBP_POTASSIUM_ION_HOMEOSTASIS, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, CTATGCA_MIR153, AAAYRNCTG_UNKNOWN, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MACROAUTOPHAGY, TTGGGAG_MIR150

GO Biological Process (13): ubiquitin-dependent protein catabolic process (GO:0006511), gene expression (GO:0010467), macroautophagy (GO:0016236), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), monoatomic ion homeostasis (GO:0050801), potassium ion homeostasis (GO:0055075), renal sodium ion absorption (GO:0070294), protein K48-linked ubiquitination (GO:0070936), distal tubule morphogenesis (GO:0072156), protein polyubiquitination (GO:0000209), protein catabolic process (GO:0030163), renal absorption (GO:0070293)

GO Molecular Function (5): actin binding (GO:0003779), structural molecule activity (GO:0005198), cullin family protein binding (GO:0097602), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), Cul3-RING ubiquitin ligase complex (GO:0031463)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	2
cellular anatomical structure	2
modification-dependent protein catabolic process	1
macromolecule biosynthetic process	1
autophagosome assembly	1
autophagy	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
chemical homeostasis	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
renal sodium ion transport	1
renal absorption	1
protein polyubiquitination	1
distal tubule development	1
nephron tubule morphogenesis	1
macromolecule catabolic process	1
protein metabolic process	1
renal system process	1
cytoskeletal protein binding	1
molecular_function	1
protein binding	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membraneless organelle	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

798 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL3	CUL3	Q13618	968
KLHL3	WNK4	Q96J92	913
KLHL3	STK39	Q9UEW8	779
KLHL3	WNK1	P54963	743
KLHL3	SLC12A3	P55017	620
KLHL3	WNK3	Q9BYP7	597
KLHL3	KCNJ1	P48048	558
KLHL3	SLC12A1	Q13621	506
KLHL3	ZNF527	Q8NB42	474
KLHL3	FBXO22	Q8NEZ5	465
KLHL3	OXSR1	O95747	454
KLHL3	KLHL31	Q9H511	445
KLHL3	STK24	Q9Y6E0	419
KLHL3	KLHL2	O95198	418
KLHL3	C13orf46	A0A1B0GUA9	417

IntAct

51 interactions, top by confidence:

A	B	Type	Score
CUL3	KLHL3	psi-mi:“MI:0915”(physical association)	0.850
KLHL3	CUL3	psi-mi:“MI:0915”(physical association)	0.850
KLHL12	KLHL3	psi-mi:“MI:0915”(physical association)	0.670
KLHL2	KLHL3	psi-mi:“MI:0915”(physical association)	0.670
KEAP1	KLHL3	psi-mi:“MI:0915”(physical association)	0.670
HRT1	KLHL3	psi-mi:“MI:0915”(physical association)	0.610
KLHL3	HRT1	psi-mi:“MI:0915”(physical association)	0.610
TNPO2	KLHL3	psi-mi:“MI:0915”(physical association)	0.560
KLHL3	CASP6	psi-mi:“MI:0915”(physical association)	0.560
KLHL3	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
KLHL3	GSN	psi-mi:“MI:0915”(physical association)	0.560
KLHL3	HRAS	psi-mi:“MI:0915”(physical association)	0.560
KLHL3	LAMP2	psi-mi:“MI:0915”(physical association)	0.560
KLF11	KLHL3	psi-mi:“MI:0915”(physical association)	0.560
DNAJB6	KLHL3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (98): KLHL3 (Affinity Capture-Western), WNK4 (Reconstituted Complex), WNK4 (Affinity Capture-Western), KLHL3 (Two-hybrid), KLHL3 (Two-hybrid), KLHL3 (Two-hybrid), KLHL3 (Two-hybrid), KLHL12 (Two-hybrid), C6orf165 (Two-hybrid), WNK1 (Biochemical Activity), CLDN8 (Affinity Capture-Western), KLHL3 (Affinity Capture-Western), KLHL3 (Affinity Capture-Western), CUL3 (Reconstituted Complex), KLHL3 (Affinity Capture-Western)

ESM2 similar proteins: A0JMG1, A2VE52, D3K5L7, E0CZ16, E1C6Q1, E2R222, F1LZ52, F1LZF0, F1MBP6, O13016, O35345, O43791, O60684, O95164, O95198, O95544, P35815, P36993, P54797, P58058, P63143, P63144, Q0IHH9, Q0V7M0, Q0VCW1, Q15645, Q28528, Q28F89, Q2M2N2, Q2TA46, Q3UA06, Q4PJK1, Q5BL35, Q5NVK7, Q5RBV0, Q5REP9, Q5U1X1, Q5XHZ9, Q6GR09, Q6IQ16

Diamond homologs: A0A0A6YY25, B2RXH4, E0CZ16, E1B932, E7F6F9, F1LZ52, F1LZF0, F1MBP6, O88282, O93567, O95198, P10074, P17789, P42282, P42283, P42284, Q01295, Q1H9T6, Q24174, Q24206, Q3B7M1, Q52KG4, Q53G59, Q53HC5, Q5R633, Q5REP9, Q5U374, Q66HD2, Q6NRH0, Q7KQZ4, Q7KRI2, Q867Z4, Q86B87, Q8BGY4, Q8BZM0, Q8CA72, Q8IN81, Q8JZP3, Q8K0L9, Q8N143

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
KLHL3	“down-regulates quantity by destabilization”	WNK1	binding
KLHL3	“up-regulates activity”	“Cullin 3-RBX1-Skp1”	binding
KLHL3	“down-regulates quantity by destabilization”	WNK4	binding
PKC	“up-regulates quantity by stabilization”	KLHL3	phosphorylation
PKA	“up-regulates activity”	KLHL3	phosphorylation
AKT	“up-regulates activity”	KLHL3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	7
Uncertain significance	228
Likely benign	39
Benign	89

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
100527	NM_017415.3(KLHL3):c.1410G>A (p.Trp470Ter)	Pathogenic
100528	NM_017415.3(KLHL3):c.721del (p.Leu241fs)	Pathogenic
100529	NM_017415.3(KLHL3):c.753+1G>A	Pathogenic
100531	NM_017415.3(KLHL3):c.1480G>A (p.Ala494Thr)	Pathogenic
100532	NM_017415.3(KLHL3):c.230C>A (p.Ala77Glu)	Pathogenic
100533	NM_017415.3(KLHL3):c.491G>T (p.Cys164Phe)	Pathogenic
100534	NM_017415.3(KLHL3):c.254A>C (p.Glu85Ala)	Pathogenic
100538	NM_017415.3(KLHL3):c.232A>G (p.Met78Val)	Pathogenic
100539	NM_017415.3(KLHL3):c.1501C>A (p.Pro501Thr)	Pathogenic
100540	NM_017415.3(KLHL3):c.430C>T (p.Gln144Ter)	Pathogenic
100541	NM_017415.3(KLHL3):c.926A>G (p.Gln309Arg)	Pathogenic
30516	NM_017415.3(KLHL3):c.965T>G (p.Phe322Cys)	Pathogenic
30517	NM_017415.3(KLHL3):c.1229C>T (p.Ser410Leu)	Pathogenic
30518	NM_017415.3(KLHL3):c.1583G>A (p.Arg528His)	Pathogenic
30519	NM_017415.3(KLHL3):c.718C>T (p.Arg240Ter)	Pathogenic
31544	NM_017415.3(KLHL3):c.1193C>T (p.Ala398Val)	Pathogenic
31545	NM_017415.3(KLHL3):c.1587C>A (p.Asn529Lys)	Pathogenic
31546	NM_017415.3(KLHL3):c.1277C>T (p.Pro426Leu)	Pathogenic
3235152	NM_017415.3(KLHL3):c.1554_1570dup (p.Asn524delinsSerLysTrpGlnThrTer)	Pathogenic
100537	NM_017415.3(KLHL3):c.1280T>C (p.Met427Thr)	Likely pathogenic
100550	NM_017415.3(KLHL3):c.1295G>A (p.Ser432Asn)	Likely pathogenic
1172819	NM_017415.3(KLHL3):c.1692G>A (p.Trp564Ter)	Likely pathogenic
1177423	NM_017415.3(KLHL3):c.1000C>T (p.Pro334Ser)	Likely pathogenic
30522	NM_017415.3(KLHL3):c.1582C>T (p.Arg528Cys)	Likely pathogenic
3591715	NM_017415.3(KLHL3):c.1291C>T (p.Arg431Trp)	Likely pathogenic
620291	NM_017415.3(KLHL3):c.139C>T (p.Gln47Ter)	Likely pathogenic

SpliceAI

3669 predictions. Top by Δscore:

Variant	Effect	Δscore
5:137625749:TGAC:T	donor_loss	1.0000
5:137625750:GAC:G	donor_loss	1.0000
5:137625751:ACCTG:A	donor_loss	1.0000
5:137625894:CCC:C	acceptor_gain	1.0000
5:137625895:CCC:C	acceptor_gain	1.0000
5:137634032:CATA:C	donor_loss	1.0000
5:137634033:ATAC:A	donor_loss	1.0000
5:137634036:C:CG	donor_loss	1.0000
5:137637292:AC:A	donor_gain	1.0000
5:137637293:CC:C	donor_gain	1.0000
5:137637315:CA:C	donor_gain	1.0000
5:137638948:CCTA:C	donor_loss	1.0000
5:137638951:A:AC	donor_gain	1.0000
5:137638952:C:CC	donor_gain	1.0000
5:137638952:C:CT	donor_loss	1.0000
5:137639148:CAC:C	acceptor_gain	1.0000
5:137639151:CTGAG:C	acceptor_loss	1.0000
5:137639152:T:A	acceptor_loss	1.0000
5:137639157:C:CT	acceptor_gain	1.0000
5:137639159:C:CT	acceptor_gain	1.0000
5:137639160:A:T	acceptor_gain	1.0000
5:137639854:GCTCA:G	donor_loss	1.0000
5:137639855:CTCA:C	donor_loss	1.0000
5:137639856:TCA:T	donor_loss	1.0000
5:137639857:CA:C	donor_loss	1.0000
5:137639859:C:CT	donor_loss	1.0000
5:137639859:CCTG:C	donor_gain	1.0000
5:137639981:C:CT	acceptor_gain	1.0000
5:137639981:C:T	acceptor_gain	1.0000
5:137639982:G:T	acceptor_gain	1.0000

AlphaMissense

3872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:137625759:A:G	Y577H	1.000
5:137625796:C:A	W564C	1.000
5:137625796:C:G	W564C	1.000
5:137625798:A:G	W564R	1.000
5:137625798:A:T	W564R	1.000
5:137625838:G:C	N550K	1.000
5:137625838:G:T	N550K	1.000
5:137625848:C:T	G547E	1.000
5:137625854:T:A	D545V	1.000
5:137625854:T:G	D545A	1.000
5:137625857:C:A	G544V	1.000
5:137625857:C:T	G544E	1.000
5:137625858:C:A	G544W	1.000
5:137625858:C:G	G544R	1.000
5:137625858:C:T	G544R	1.000
5:137625860:C:A	G543V	1.000
5:137625860:C:T	G543E	1.000
5:137625861:C:G	G543R	1.000
5:137625861:C:T	G543R	1.000
5:137628301:G:C	N529K	1.000
5:137628301:G:T	N529K	1.000
5:137628302:T:A	N529I	1.000
5:137628303:T:C	N529D	1.000
5:137628305:C:G	R528P	1.000
5:137628306:G:T	R528S	1.000
5:137628308:C:G	R527P	1.000
5:137628309:G:C	R527G	1.000
5:137628337:C:A	W517C	1.000
5:137628337:C:G	W517C	1.000
5:137628338:C:G	W517S	1.000

dbSNP variants (sampled 300 via entrez): RS1000033644 (5:137621478 G>C), RS1000051960 (5:137630521 G>A), RS1000105822 (5:137669113 G>A), RS1000118957 (5:137684391 G>A), RS1000147673 (5:137667449 T>A,C), RS1000154874 (5:137620604 C>T), RS1000171977 (5:137723836 T>A), RS1000204479 (5:137723378 A>G), RS1000212051 (5:137674725 G>A), RS1000279879 (5:137676446 C>T), RS1000309591 (5:137681681 G>A), RS1000340516 (5:137681435 C>G), RS1000354239 (5:137731388 C>T), RS1000400739 (5:137628554 T>C), RS1000428678 (5:137633840 T>C,G)

Disease associations

OMIM: gene MIM:605775 | disease phenotypes: MIM:145260, MIM:614495

GenCC curated gene-disease

Disease	Classification	Inheritance
pseudohypoaldosteronism type 2D	Strong	Autosomal dominant

Mondo (3): pseudohypoaldosteronism type 2A (MONDO:0007772), pseudohypoaldosteronism type 2D (MONDO:0013781), cerebral palsy (MONDO:0006497)

Orphanet (3): Pseudohypoaldosteronism type 2D (Orphanet:300525), Pseudohypoaldosteronism type 2 (Orphanet:757), Pseudohypoaldosteronism type 2A (Orphanet:88938)

HPO phenotypes

8 total (9 of 8 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000822	Hypertension
HP:0002153	Hyperkalemia
HP:0004918	Hyperchloremic metabolic acidosis
HP:0008242	Pseudohypoaldosteronism
HP:0011423	Hyperchloremia
HP:0011462	Young adult onset
HP:0100021	Cerebral palsy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002104_20	Bronchopulmonary dysplasia	9.000000e-06
GCST005356_12	Severe malaria	6.000000e-07
GCST005357_8	Severe malaria (adjusted for sickle cell variant rs334)	2.000000e-06
GCST009541_3	Heart failure	2.000000e-08
GCST90002384_114	Hemoglobin	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066208 (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
6.17	Kd	670	nM	CHEMBL5611958
6.16	Kd	690	nM	CHEMBL5613311

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 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
(4S)-4-amino-5-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(1S)-1-carboxy-2-methylpropyl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid	2124192: Binding affinity to human N-terminal KLHL3 (290 to 587 residues) extracted from Escherichia coli BL21 (DE3) assessed as dissociation constant by fluorescence polarization assay	kd	0.6700	uM
(4S)-4-amino-5-[(2S)-2-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(1S)-4-amino-1-carboxy-4-oxobutyl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-5-oxopentanoic acid	2124191: Binding affinity to KLHL3 (unknown origin) assessed as dissociation constant by fluorescence polarization assay	kd	0.6900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression, decreases methylation	3
Valproic Acid	affects expression, decreases expression	3
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
ochratoxin A	increases expression	1
M-VAC protocol	decreases response to substance	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cannabidiol	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Aflatoxin B1	decreases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	increases expression, increases abundance	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5608432	Binding	Binding affinity to KLHL3 (unknown origin) assessed as dissociation constant by fluorescence polarization assay	Targeting kelch-like (KLHL) proteins: achievements, challenges and perspectives. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SU95	HAP1 KLHL3 (-) 1	Cancer cell line	Male
CVCL_SU96	HAP1 KLHL3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02839785	PHASE3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	PHASE3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A
NCT03306212	PHASE3	COMPLETED	Efficacy of Intermittent Serial Casting on Spastic Wrist Flexion Deformity