WNK3

Summary

WNK3 (WNK lysine deficient protein kinase 3, HGNC:14543) is a protein-coding gene on chromosome Xp11.22, encoding Serine/threonine-protein kinase WNK3 (Q9BYP7). Serine/threonine-protein kinase component of the WNK3-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis and regulatory volume increase in response to hyperosmotic stress.

This gene encodes a protein belonging to the ‘with no lysine’ family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase-3-dependent pathway. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 65267 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Prieto syndrome (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 378 total — 8 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_020922

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14543
Approved symbol	WNK3
Name	WNK lysine deficient protein kinase 3
Location	Xp11.22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196632
Ensembl biotype	protein_coding
OMIM	300358
Entrez	65267

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000354646, ENST00000375169, ENST00000458404, ENST00000886258, ENST00000919395, ENST00000919396, ENST00000919397

RefSeq mRNA: 3 — MANE Select: NM_020922 NM_001002838, NM_001395166, NM_020922

CCDS: CCDS14357, CCDS35302

Canonical transcript exons

ENST00000354646 — 24 exons

Exon	Start	End
ENSE00000821360	54201991	54202193
ENSE00000821361	54232809	54233020
ENSE00000821362	54236938	54237551
ENSE00000821363	54238342	54238472
ENSE00000821365	54248697	54249634
ENSE00000821366	54249994	54250131
ENSE00000821367	54251399	54251450
ENSE00000821368	54251532	54251687
ENSE00000821369	54253959	54254075
ENSE00000821370	54255740	54255887
ENSE00000821371	54259274	54259338
ENSE00000821372	54292888	54293037
ENSE00000821373	54293134	54293327
ENSE00000821374	54294553	54294847
ENSE00000893248	54301771	54301859
ENSE00001093907	54298175	54298394
ENSE00001190292	54238868	54239099
ENSE00001295408	54311119	54311291
ENSE00001304962	54333137	54333792
ENSE00001315413	54228714	54228743
ENSE00001318963	54309095	54309315
ENSE00001324912	54307922	54308079
ENSE00001825071	54192823	54198653
ENSE00004020332	54357686	54358046

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 98.43.

FANTOM5 (CAGE): breadth broad, TPM avg 4.4591 / max 197.8845, expressed in 663 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199388	3.9729	626
199387	0.4862	248

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	98.43	gold quality
buccal mucosa cell	CL:0002336	95.42	gold quality
cauda epididymis	UBERON:0004360	94.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.88	gold quality
cortical plate	UBERON:0005343	81.93	gold quality
oviduct epithelium	UBERON:0004804	81.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.32	gold quality
caput epididymis	UBERON:0004358	80.23	gold quality
secondary oocyte	CL:0000655	78.00	gold quality
seminal vesicle	UBERON:0000998	77.97	gold quality
medial globus pallidus	UBERON:0002477	77.95	gold quality
pigmented layer of retina	UBERON:0001782	77.81	gold quality
testis	UBERON:0000473	77.72	gold quality
right testis	UBERON:0004534	76.98	gold quality
ventricular zone	UBERON:0003053	76.19	gold quality
left testis	UBERON:0004533	75.71	gold quality
substantia nigra pars compacta	UBERON:0001965	75.68	silver quality
ganglionic eminence	UBERON:0004023	75.56	gold quality
postcentral gyrus	UBERON:0002581	75.23	gold quality
endothelial cell	CL:0000115	74.82	silver quality
parietal lobe	UBERON:0001872	74.08	gold quality
adrenal tissue	UBERON:0018303	73.96	gold quality
globus pallidus	UBERON:0001875	73.73	gold quality
superior vestibular nucleus	UBERON:0007227	73.33	gold quality
substantia nigra pars reticulata	UBERON:0001966	72.80	silver quality
middle temporal gyrus	UBERON:0002771	72.68	gold quality
Brodmann (1909) area 46	UBERON:0006483	72.41	gold quality
superior frontal gyrus	UBERON:0002661	72.13	gold quality
liver	UBERON:0002107	71.91	gold quality
entorhinal cortex	UBERON:0002728	71.89	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.96
E-HCAD-38	no	213.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

378 targeting WNK3, 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-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-511-3P	99.99	68.85	1467

Literature-anchored findings (GeneRIF, showing 22)

• WNK3 lies within the critical linkage interval for several human monogenic disorders, including X-linked mental retardation. The function of mammalian WNK3 kinase remains to be investigated. (PMID:15194194)
• WNK3 is involved in promoting cell survival by a mechanism at the level of procaspase-3 activation. (PMID:16501604)
• Results report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes. (PMID:17975670)
• Xp11.22 deletion including genes PHF8, FAM120C and WNK3 may be involved in the pathogenesis of autism. (PMID:18498374)
• The positive effect of WNK3 on NCC also requires its catalytic activity (PMID:18701621)
• WNK3 is a positive regulator of the transcellular Ca2+ transport pathway (TRPV5 and TRPV6). (PMID:18768590)
• The C-terminal motifs contributed by exons 18 and 22 play an important role in the actions of WNK3 isoforms on NCCT. (PMID:19470686)
• Data find that expression of the N termini of all four WNKs results in modest to strong activation of SGK1. (PMID:20525693)
• OXSR1 and WNK3 transcripts were substantially overexpressed in subjects with schizophrenia relative to comparison subjects. (PMID:20819979)
• The Wnk3 protein isoforms have a similar effect on SLC12 cotransporters. NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. (PMID:21613606)
• Analysis of the data showed that WNK3 is an essential regulator of NKCC1 and that WNK3 activates NKCC1-mediated ion transport necessary for cell volume changes associated with cell invasion. (PMID:21813709)
• WNK3 modulates intracellular Cl(-) concentration and regulatory volume decrease in HEK293 cells. (PMID:22864523)
• LINGO-1 potentiates neuronal apoptosis, likely by inhibiting WNK3 kinase activity. (PMID:23482566)
• There may be a novel role for WNK3 on the renal Na+-Cl-cotransporter (NCC) expression at the plasma membrane, an effect apparently independent of the SPAK kinase and the aldosterone-SGK1 pathway. (PMID:24920754)
• WNK3 knockout mice exhibited significantly decreased infarct volume in a transgenic model of stroke and brain damage. (PMID:26069258)
• Data show that WNK lysine deficient protein kinase 3 protein (WNK3) interacts with NCC and increases the Na-Cl cotransporter (NCC) expression on the cell membrane and in cytoplasm together. (PMID:27378340)
• WNK3 enhances NCC protein expression by increasing NCC synthesis via an ERK 1/2-dependent signaling pathway (PMID:27467688)
• This study demonstrated that the WNK3 up regulation in hippocampal specimens from epileptic patients with hippocampal sclerosis. (PMID:30253317)
• A Phosphorylated Intermediate in the Activation of WNK Kinases. (PMID:32314908)
• WNKs are potassium-sensitive kinases. (PMID:33439774)
• Advances in the study of the role and molecular mechanism of withnolysine kinase 3 in nervous system diseases (Review). (PMID:33760209)
• WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function. (PMID:36357569)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	wnk3	ENSDARG00000021611
mus_musculus	Wnk3	ENSMUSG00000041245
rattus_norvegicus	Wnk3	ENSRNOG00000002537
drosophila_melanogaster	Madm	FBGN0027497
drosophila_melanogaster	Wnk	FBGN0037098
caenorhabditis_elegans		WBGENE00006941
caenorhabditis_elegans	hpo-11	WBGENE00010427

Paralogs (6): WNK1 (ENSG00000060237), NRBP1 (ENSG00000115216), WNK4 (ENSG00000126562), DSTYK (ENSG00000133059), WNK2 (ENSG00000165238), NRBP2 (ENSG00000185189)

Protein

Protein identifiers

Serine/threonine-protein kinase WNK3 — Q9BYP7 (reviewed: Q9BYP7)

Alternative names: Protein kinase lysine-deficient 3, Protein kinase with no lysine 3

All UniProt accessions (2): Q9BYP7, B1AQN8

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase component of the WNK3-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis and regulatory volume increase in response to hyperosmotic stress. WNK3 mediates regulatory volume increase in response to hyperosmotic stress by acting as a molecular crowding sensor, which senses cell shrinkage and mediates formation of a membraneless compartment by undergoing liquid-liquid phase separation. The membraneless compartment concentrates WNK3 with its substrates, OXSR1/OSR1 and STK39/SPAK, promoting WNK3-dependent phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK. Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A4/KCC1, SLC12A5/KCC2 or SLC12A6/KCC3, regulating their activity. Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx; simultaneously, phosphorylation of K-Cl cotransporters SLC12A4/KCC1, SLC12A5/KCC2 and SLC12A6/KCC3 inhibits its activity, blocking ion efflux. Phosphorylates WNK4, possibly regulating the activity of SLC12A3/NCC. May also phosphorylate NEDD4L. Also acts as a scaffold protein independently of its protein kinase activity: negatively regulates cell membrane localization of various transporters and channels, such as KCNJ1 and SLC26A9. Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway.

Subunit / interactions. Interacts with WNK1 and WNK4.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in brain, lung, kidney, liver and pancreas, and in fetal tissues including placenta, fetal brain, lung and kidney. Very low levels of expression were also detected in fetal heart, thymus, liver and spleen. Isoform 1 is brain-specific. Isoform 3 is kidney-specific.

Post-translational modifications. Autophosphorylated at Ser-304 and Ser-308, promoting its activity. Phosphorylation at Thr-541 prevents interaction with KLHL3 and subsequent ubiquitination and degradation by the BCR(KLHL3) complex. Ubiquitinated by the BCR(KLHL2) complex, leading to its degradation. Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation.

Disease relevance. Prieto syndrome (PRS) [MIM:309610] An X-linked recessive disorder characterized by impaired intellectual development, developmental delay, autism spectrum disorder, variable epilepsy, craniofacial dysmorphism, and structural brain abnormalities including polymicrogyria and cerebral atrophy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated in response to hyperosmotic stress: cell shrinkage promotes formation of a membraneless compartment that concentrates WNK3 with its substrates, OXSR1/OSR1 and STK39/SPAK. Activation requires autophosphorylation of Ser-308 and, to a lower extent, Ser-304. Autophosphorylation and subsequent activation is inhibited by increases in intracellular ionic strength: Cl(-) potently inhibits WNK3 kinase activity via direct binding. Also inhibited by K(+) ions. Kinase activity is inhibited by WNK4.

Domain organisation. Disordered regions undergo liquid-liquid phase separation (LLPS) for the formation of a cytoplasmic membraneless compartment that concentrates WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9BYP7-1	1	yes
Q9BYP7-2	2
Q9BYP7-3	3
Q9BYP7-4	4

RefSeq proteins (3): NP_001002838, NP_001382095, NP_065973* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR024678	Kinase_OSR1/WNK_CCT	Domain
IPR050588	WNK_Ser-Thr_kinase	Family
IPR056865	CCTL2_WNK	Domain

Pfam: PF00069, PF12202, PF24889

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (87 total): helix 22, strand 14, sequence variant 11, region of interest 9, modified residue 7, compositionally biased region 6, mutagenesis site 4, turn 4, sequence conflict 3, binding site 2, splice variant 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5O1V	X-RAY DIFFRACTION	1.72
5O2B	X-RAY DIFFRACTION	2.04
5O21	X-RAY DIFFRACTION	2.06
5O23	X-RAY DIFFRACTION	2.25
5O26	X-RAY DIFFRACTION	2.38
5O2C	X-RAY DIFFRACTION	2.4
5NKP	X-RAY DIFFRACTION	2.8
8EDH	X-RAY DIFFRACTION	3.11
9D7Q	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYP7-F1	48.31	0.14

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 294 (proton acceptor)

Ligand- & substrate-binding residues (2): 227–230; 277

Post-translational modifications (7): 62, 304, 308, 541, 1070, 1585, 1638

Mutagenesis-validated functional residues (4):

Position	Phenotype
159	abolished serine/threonine-protein kinase activity without affecting ability to regulate localization of slc12a9.
294	catalytically inactive form. inhibits sodium-coupled chloride cotransporters and activates potassium-coupled chloride co
541	impaired interaction with klhl3.
541	mimics phosphorylation, leading to decreased interaction with klhl3 and subsequent ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 372 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_DIGESTION, GOBP_REGULATION_OF_PHOSPHORYLATION, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_HYPEROSMOTIC_RESPONSE, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_SODIUM_ION_TRANSPORT

GO Biological Process (21): protein phosphorylation (GO:0006468), cell volume homeostasis (GO:0006884), DNA damage response (GO:0006974), osmosensory signaling pathway (GO:0007231), positive regulation of sodium ion transport (GO:0010765), positive regulation of peptidyl-threonine phosphorylation (GO:0010800), intracellular signal transduction (GO:0035556), maintenance of blood-brain barrier (GO:0035633), negative regulation of apoptotic process (GO:0043066), monoatomic ion homeostasis (GO:0050801), positive regulation of calcium ion transport (GO:0051928), renal sodium ion absorption (GO:0070294), cellular hyperosmotic response (GO:0071474), protein localization to plasma membrane (GO:0072659), negative regulation of pancreatic juice secretion (GO:0090188), regulation of calcium ion import (GO:0090279), membraneless organelle assembly (GO:0140694), negative regulation of protein localization to plasma membrane (GO:1903077), positive regulation of protein localization to plasma membrane (GO:1903078), regulation of monoatomic cation transmembrane transport (GO:1904062), positive regulation of sodium ion transmembrane transporter activity (GO:2000651)

GO Molecular Function (11): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), transmembrane transporter binding (GO:0044325), protein serine kinase activity (GO:0106310), molecular condensate scaffold activity (GO:0140693), transporter activator activity (GO:0141109), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): cytoplasm (GO:0005737), adherens junction (GO:0005912), bicellular tight junction (GO:0005923)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to osmotic stress	2
positive regulation of monoatomic ion transport	2
intracellular anatomical structure	2
regulation of calcium ion transport	2
protein localization to plasma membrane	2
regulation of protein localization to plasma membrane	2
protein kinase activity	2
phosphorylation	1
protein modification process	1
regulation of cell size	1
cellular homeostasis	1
cellular response to stress	1
intracellular signal transduction	1
regulation of sodium ion transport	1
sodium ion transport	1
positive regulation of protein phosphorylation	1
regulation of peptidyl-threonine phosphorylation	1
peptidyl-threonine phosphorylation	1
signal transduction	1
tissue homeostasis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
chemical homeostasis	1
calcium ion transport	1
renal sodium ion transport	1
renal absorption	1
hyperosmotic response	1
protein localization to membrane	1
protein localization to cell periphery	1
pancreatic juice secretion	1
negative regulation of secretion	1
negative regulation of digestive system process	1
regulation of pancreatic juice secretion	1
calcium ion import	1
organelle assembly	1
negative regulation of protein localization to cell periphery	1
negative regulation of protein localization to membrane	1
positive regulation of protein localization to cell periphery	1
positive regulation of protein localization to membrane	1

Protein interactions and networks

STRING

992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WNK3	SLC12A3	P55017	909
WNK3	SLC12A2	P55011	905
WNK3	SLC12A5	Q9H2X9	884
WNK3	SLC12A1	Q13621	874
WNK3	SLC12A4	Q9UP95	858
WNK3	KCNJ1	P48048	844
WNK3	FAM120C	Q9NX05	813
WNK3	PHF8	Q9UPP1	716
WNK3	FGD3	Q5JSP0	710
WNK3	SLC12A6	Q9UHW9	658
WNK3	WNK1	P54963	652
WNK3	SLC12A7	Q9Y666	636
WNK3	ITSN1	Q15811	600
WNK3	KLHL3	Q9UH77	597
WNK3	NEDD4L	Q96PU5	567

IntAct

30 interactions, top by confidence:

A	B	Type	Score
OPG044	DDX3X	psi-mi:“MI:0914”(association)	0.730
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
LBX1	WNK3	psi-mi:“MI:0915”(physical association)	0.560
REL	WNK3	psi-mi:“MI:0915”(physical association)	0.560
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
CASP3	WNK3	psi-mi:“MI:0915”(physical association)	0.520
WNK3	CASP3	psi-mi:“MI:0915”(physical association)	0.520
WNK3	H1-5	psi-mi:“MI:0915”(physical association)	0.400
WNK3	CCT7	psi-mi:“MI:0915”(physical association)	0.400
WNK3	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
HMGN5	SMCHD1	psi-mi:“MI:0914”(association)	0.350
OXSR1	RBM25	psi-mi:“MI:0914”(association)	0.350
PPM1G	SRP14	psi-mi:“MI:0914”(association)	0.350
WNK1	XPO1	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
KLHL2	DCTN6	psi-mi:“MI:0914”(association)	0.350
TSC22D4	PSMA7	psi-mi:“MI:0914”(association)	0.350
TGM7	HGS	psi-mi:“MI:0914”(association)	0.350
TSC22D4	TBL1X	psi-mi:“MI:0914”(association)	0.350
KCNK3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
YWHAH	E2F8	psi-mi:“MI:2364”(proximity)	0.270
WNK3	LBX1	psi-mi:“MI:0915”(physical association)	0.000
WNK3	REL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (75): WNK3 (Affinity Capture-MS), WNK3 (Two-hybrid), WNK3 (Affinity Capture-MS), WNK3 (Affinity Capture-MS), WNK3 (Affinity Capture-MS), WNK3 (Affinity Capture-MS), WNK3 (Two-hybrid), WNK3 (Two-hybrid), WNK3 (Proximity Label-MS), WNK3 (Proximity Label-MS), WNK3 (Proximity Label-MS), WNK3 (Proximity Label-MS), WNK3 (Proximity Label-MS), WNK3 (Proximity Label-MS), WNK3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0A6YYL3, A1ZAC4, A6QP06, A8C984, B3NLX1, D2HXI8, E1BFR5, E1C2I2, E2RJI4, F4JQ51, F4JXF1, F4KBP5, H3BUK9, O08815, O54988, O55092, P15792, P20689, P51954, P51957, Q3UVR3, Q4R7T5, Q5RD27, Q5ZMS4, Q60DG4, Q61IS6, Q696W0, Q6NTJ3, Q6YY75, Q7TSC3, Q80XP9, Q8BI55, Q8C0P0, Q8N157, Q8N573, Q8NI08, Q8VCR8, Q94CU5, Q96GX5, Q96PY6

Diamond homologs: A0A078CGE6, A2AQW0, A2QHV0, A2YMV6, A9RVK2, A9SY39, C4YRB7, D4A280, M9PGC5, O14305, O24527, O75914, O81472, O88643, P0CY23, P0CY24, P35465, P41892, P83741, Q01577, Q03497, Q08E52, Q0CL79, Q0D541, Q0D598, Q0D847, Q13153, Q13177, Q17850, Q21029, Q29502, Q297L2, Q2QXC6, Q2QYL8, Q2RA93, Q2RBE3, Q2ULU3, Q2V338, Q2VWQ3, Q39008

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
WNK3	“up-regulates activity”	WNK1	phosphorylation
WNK3	“down-regulates activity”	SLC12A6	phosphorylation
KLHL2	“down-regulates quantity by destabilization”	WNK3	binding
“Cullin 3-RBX1-Skp1”	“down-regulates quantity by destabilization”	WNK3	polyubiquitination
WNK3	“up-regulates activity”	SLC12A3	phosphorylation
WNK3	“up-regulates activity”	SLC12A2	phosphorylation
WNK3	“up-regulates activity”	SLC12A1	phosphorylation
WNK3	“down-regulates activity”	SLC12A4	phosphorylation
WNK3	“down-regulates activity”	SLC12A5	phosphorylation
WNK3	“down-regulates activity”	SLC12A7	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	2
Uncertain significance	192
Likely benign	33
Benign	13

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1344898	NM_020922.5(WNK3):c.538-2A>G	Pathogenic
1344899	NM_020922.5(WNK3):c.611C>G (p.Pro204Arg)	Pathogenic
1344900	NM_020922.5(WNK3):c.721C>T (p.Arg241Ter)	Pathogenic
1344901	NM_020922.5(WNK3):c.899T>C (p.Leu300Ser)	Pathogenic
1344902	NM_020922.5(WNK3):c.1089+1G>A	Pathogenic
1344903	NM_020922.5(WNK3):c.1820A>T (p.Glu607Val)	Pathogenic
3774998	NM_020922.5(WNK3):c.4978G>T (p.Glu1660Ter)	Pathogenic
4077050	NM_020922.5(WNK3):c.1228G>T (p.Gly410Ter)	Pathogenic
2570654	NM_020922.5(WNK3):c.4000dup (p.Arg1334fs)	Likely pathogenic
3390281	NM_020922.5(WNK3):c.1162C>T (p.Gln388Ter)	Likely pathogenic

SpliceAI

4626 predictions. Top by Δscore:

Variant	Effect	Δscore
X:54198508:CAAA:C	donor_gain	1.0000
X:54201986:CTT:C	donor_loss	1.0000
X:54201987:TTA:T	donor_loss	1.0000
X:54201988:TAC:T	donor_loss	1.0000
X:54201989:A:AC	donor_gain	1.0000
X:54201989:ACTT:A	donor_gain	1.0000
X:54201990:C:CT	donor_gain	1.0000
X:54201990:CT:C	donor_gain	1.0000
X:54201990:CTT:C	donor_gain	1.0000
X:54201990:CTTC:C	donor_gain	1.0000
X:54202079:A:AC	donor_gain	1.0000
X:54202080:C:CC	donor_gain	1.0000
X:54202080:CTG:C	donor_gain	1.0000
X:54202085:T:TA	donor_gain	1.0000
X:54202189:TGGAT:T	acceptor_gain	1.0000
X:54202190:GGAT:G	acceptor_gain	1.0000
X:54202191:GAT:G	acceptor_gain	1.0000
X:54202193:TC:T	acceptor_loss	1.0000
X:54202194:C:CC	acceptor_gain	1.0000
X:54202196:A:C	acceptor_gain	1.0000
X:54202202:C:CT	acceptor_gain	1.0000
X:54232805:TTACC:T	donor_loss	1.0000
X:54232806:TA:T	donor_loss	1.0000
X:54233016:TGTGT:T	acceptor_gain	1.0000
X:54233017:GTGT:G	acceptor_gain	1.0000
X:54233018:TGT:T	acceptor_gain	1.0000
X:54233019:GT:G	acceptor_gain	1.0000
X:54233020:TC:T	acceptor_loss	1.0000
X:54233021:C:CC	acceptor_gain	1.0000
X:54236936:A:AC	donor_gain	1.0000

AlphaMissense

11784 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:54236944:C:G	R1541P	1.000
X:54254038:A:G	L763P	1.000
X:54307935:C:G	R359P	1.000
X:54307939:A:C	Y358D	1.000
X:54307947:G:T	A355D	1.000
X:54307958:A:C	C351W	1.000
X:54307960:A:G	C351R	1.000
X:54307995:A:G	L339P	1.000
X:54308000:A:C	C337W	1.000
X:54308007:C:T	G335E	1.000
X:54308008:C:G	G335R	1.000
X:54308008:C:T	G335R	1.000
X:54308066:A:C	F315L	1.000
X:54308066:A:T	F315L	1.000
X:54308067:A:G	F315S	1.000
X:54308068:A:G	F315L	1.000
X:54309172:C:T	G285E	1.000
X:54309173:C:G	G285R	1.000
X:54309173:C:T	G285R	1.000
X:54309178:A:T	I283N	1.000
X:54309267:C:A	W253C	1.000
X:54309267:C:G	W253C	1.000
X:54309269:A:G	W253R	1.000
X:54309269:A:T	W253R	1.000
X:54311132:C:A	G233W	1.000
X:54311143:A:G	L229P	1.000
X:54311209:A:T	V207D	1.000
X:54333151:A:G	W175R	1.000
X:54333151:A:T	W175R	1.000
X:54333156:A:T	V173D	1.000

dbSNP variants (sampled 300 via entrez): RS1000010948 (X:54231007 T>C), RS1000037293 (X:54200843 T>A), RS1000048494 (X:54231736 C>G,T), RS1000149406 (X:54312687 C>G), RS1000196185 (X:54259142 G>A,T), RS1000245354 (X:54273253 A>T), RS1000269196 (X:54204889 G>A), RS1000272951 (X:54242230 T>G), RS1000297820 (X:54273666 T>G), RS1000402507 (X:54332578 C>T), RS1000415543 (X:54332953 A>G), RS1000440496 (X:54194075 C>T), RS1000452809 (X:54302379 C>T), RS1000474820 (X:54194459 T>G), RS1000549982 (X:54341533 T>C)

Disease associations

OMIM: gene MIM:300358 | disease phenotypes: MIM:309610, MIM:209850, MIM:150280

GenCC curated gene-disease

Disease	Classification	Inheritance
Prieto syndrome	Strong	X-linked

Mondo (5): neurodevelopmental disorder (MONDO:0700092), Prieto syndrome (MONDO:0010667), autism (MONDO:0005260), sleep apnea syndrome (MONDO:0005296), congenital laryngomalacia (MONDO:0007878)

Orphanet (3): X-linked intellectual disability-dysmorphism-cerebral atrophy syndrome (Orphanet:2958), Congenital laryngomalacia (Orphanet:2373), Motor stereotypies (Orphanet:306765)

HPO phenotypes

26 total (28 of 26 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000164	Abnormality of the dentition
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000448	Prominent nose
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000639	Nystagmus
HP:0000878	11 pairs of ribs
HP:0000939	Osteoporosis
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001290	Generalized hypotonia
HP:0001419	X-linked recessive inheritance
HP:0001762	Talipes equinovarus
HP:0002059	Cerebral atrophy
HP:0002673	Coxa valga
HP:0002999	Patellar dislocation
HP:0009466	Radial deviation of finger
HP:0010499	Patellar subluxation
HP:0010781	Skin dimple
HP:0030084	Clinodactyly
HP:0000717	Autism
HP:0010535	Sleep apnea

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008163_10	Height	4.000000e-06

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D055092	Laryngomalacia	C05.182.310; C08.360.563; C09.400.563; C16.131.621.568; C17.300.182.310
D065886	Neurodevelopmental Disorders	F03.625
D012891	Sleep Apnea Syndromes	C08.618.085.852; C10.886.425.800.750
C535274	Prieto X-linked mental retardation syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6055 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,738 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1976040	ADAVOSERTIB	2	1,738

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Wnk family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 2c [PMID: 24900538]	Inhibition	7.0	pIC50

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.01	IC50	97	nM	CHEMBL4281823
7.00	IC50	99.8	nM	CHEMBL2151321
6.40	IC50	401	nM	CHEMBL2380845
6.31	IC50	494	nM	CHEMBL4793380
5.64	IC50	2310	nM	ADAVOSERTIB

PubChem BioAssay actives

6 with measured affinity, of 445 total; 6 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
1-[5-(4-amino-7-ethylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethoxy)phenyl]ethanone	1415201: Inhibition of recombinant human WNK3 (1 to 434 residues) using myelin basic protein as substrate after 40 mins in presence of [gamma-33P]-ATP by scintillation counting analysis	ic50	0.0970	uM
N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-3-(3-propan-2-yloxy-1H-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine	692425: Inhibition of WNK3	ic50	0.0998	uM
[2-[(4-chlorophenyl)methoxy]phenyl]-[5-[2-(methylamino)-1,3-thiazol-4-yl]-2,3-dihydroindol-1-yl]methanone	1802280: WNK In Vitro Radiometric Assays from Article 10.1021/acschembio.6b00511: “Discovery and Characterization of Allosteric WNK Kinase Inhibitors.”	ic50	0.3770	uM
N-[4-[(6-oxo-5H-benzo[c][1,8]naphthyridin-1-yl)amino]phenyl]benzamide	746813: Inhibition of WNK3 (unknown origin)	ic50	0.4010	uM
1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-(6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-ylamino)phenyl]urea	1735619: Inhibition of recombinant human WNK3 (1 to 434 residues) using myelin basic protein as substrate incubated for 40 mins in presence of [gamma33P]ATP by scintillation counting based radiometry assay	ic50	0.4940	uM
1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one	1531930: Inhibition of human WNK3 using MBP as substrate by [gamma-33P]-ATP assay	ic50	2.3100	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression	6
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Aflatoxin B1	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methyleugenol	decreases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation, increases methylation	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	decreases expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Acetaminophen	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Methapyrilene	decreases methylation	1
N-Nitrosopyrrolidine	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	increases expression	1

ChEMBL screening assays

142 unique, capped per target: 142 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1043844	Binding	Residual activity of WNK3 at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TY11	HAP1 WNK3 (-) 1	Cancer cell line	Male
CVCL_TY12	HAP1 WNK3 (-) 2	Cancer cell line	Male
CVCL_TY13	HAP1 WNK3 (-) 3	Cancer cell line	Male
CVCL_TY14	HAP1 WNK3 (-) 4	Cancer cell line	Male
CVCL_TY15	HAP1 WNK3 (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice