WNK1

Summary

WNK1 (WNK lysine deficient protein kinase 1, HGNC:14540) is a protein-coding gene on chromosome 12p13.33, encoding Serine/threonine-protein kinase WNK1 (Q9H4A3). Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx. It is a selective cancer dependency (DepMap: 83.5% of cell lines).

This gene encodes a member of the WNK subfamily of serine/threonine protein kinases. The encoded protein may be a key regulator of blood pressure by controlling the transport of sodium and chloride ions. Mutations in this gene have been associated with pseudohypoaldosteronism type II and hereditary sensory neuropathy type II. Alternatively spliced transcript variants encoding different isoforms have been described but the full-length nature of all of them has yet to be determined.

Source: NCBI Gene 65125 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuropathy, hereditary sensory and autonomic, type 2A (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 2,369 total — 59 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 83.5% of screened cell lines
• MANE Select transcript: NM_018979

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14540
Approved symbol	WNK1
Name	WNK lysine deficient protein kinase 1
Location	12p13.33
Locus type	gene with protein product
Status	Approved
Aliases	HSAN2, PPP1R167
Ensembl gene	ENSG00000060237
Ensembl biotype	protein_coding
OMIM	605232
Entrez	65125

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 22 protein_coding, 7 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000315939, ENST00000340908, ENST00000447667, ENST00000530271, ENST00000534872, ENST00000535572, ENST00000535698, ENST00000537603, ENST00000537687, ENST00000540360, ENST00000540885, ENST00000542424, ENST00000542543, ENST00000544559, ENST00000545055, ENST00000545285, ENST00000574679, ENST00000674810, ENST00000675236, ENST00000675631, ENST00000676347, ENST00000899150, ENST00000899151, ENST00000899152, ENST00000899153, ENST00000899154, ENST00000899155, ENST00000899156, ENST00000899157, ENST00000928791

RefSeq mRNA: 4 — MANE Select: NM_018979 NM_001184985, NM_014823, NM_018979, NM_213655

CCDS: CCDS53731, CCDS73419, CCDS8506

Canonical transcript exons

ENST00000315939 — 28 exons

Exon	Start	End
ENSE00000437674	827042	827262
ENSE00000438055	883774	883831
ENSE00000711927	813642	813814
ENSE00000711974	830003	830160
ENSE00000711996	883395	883568
ENSE00000711998	884121	884243
ENSE00000711999	884649	886084
ENSE00000712018	887221	887304
ENSE00000712020	889140	889223
ENSE00000712021	890453	890513
ENSE00000712022	894562	894635
ENSE00000712023	896071	896732
ENSE00000816769	861013	861343
ENSE00000816772	900476	900670
ENSE00000893365	871265	871348
ENSE00000893367	879573	880031
ENSE00000893368	907847	908034
ENSE00001160360	880721	880999
ENSE00001160367	878212	878361
ENSE00001160380	862083	862270
ENSE00001527897	908475	911452
ENSE00003549062	882943	883059
ENSE00003562179	881692	881789
ENSE00003605117	881911	882073
ENSE00003642281	857161	857249
ENSE00003643379	859245	859464
ENSE00003670093	897479	897681
ENSE00003847370	752579	754324

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.5464 / max 952.2894, expressed in 1823 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123315	56.5512	1820
123317	2.6330	748
123325	0.5477	101
123318	0.3975	192
123316	0.3694	148
123326	0.0476	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
medial globus pallidus	UBERON:0002477	99.42	gold quality
globus pallidus	UBERON:0001875	99.36	gold quality
inferior vagus X ganglion	UBERON:0005363	99.28	gold quality
subthalamic nucleus	UBERON:0001906	99.18	gold quality
lateral globus pallidus	UBERON:0002476	99.12	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.12	gold quality
cranial nerve II	UBERON:0000941	99.09	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.97	gold quality
trabecular bone tissue	UBERON:0002483	98.92	gold quality
substantia nigra pars compacta	UBERON:0001965	98.74	gold quality
medulla oblongata	UBERON:0001896	98.73	gold quality
inferior olivary complex	UBERON:0002127	98.67	gold quality
ventral tegmental area	UBERON:0002691	98.46	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.46	gold quality
superior vestibular nucleus	UBERON:0007227	98.44	gold quality
heart right ventricle	UBERON:0002080	98.43	gold quality
corpus callosum	UBERON:0002336	98.33	gold quality
cauda epididymis	UBERON:0004360	98.31	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.25	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.21	gold quality
nipple	UBERON:0002030	98.19	gold quality
renal medulla	UBERON:0000362	98.05	gold quality
midbrain	UBERON:0001891	98.02	gold quality
spinal cord	UBERON:0002240	97.98	gold quality
gluteal muscle	UBERON:0002000	97.97	gold quality
substantia nigra	UBERON:0002038	97.96	gold quality
sural nerve	UBERON:0015488	97.95	gold quality
tendon of biceps brachii	UBERON:0008188	97.84	gold quality
caput epididymis	UBERON:0004358	97.82	gold quality
biceps brachii	UBERON:0001507	97.73	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	2932.03
E-MTAB-9221	yes	786.63
E-HCAD-9	yes	6.09
E-CURD-135	no	2995.13
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, SP1

miRNA regulators (miRDB)

195 targeting WNK1, 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-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6130	100.00	66.69	2012
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-6133	100.00	66.48	2064
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AT-5P	99.96	70.83	2666

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 83.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• identification of autoinhibitory domain (PMID:12374799)
• Protein kinase B mediates the phosphorylation of WNK1 at Thr-60. (PMID:14611643)
• control of kidney WNK1 gene expression of kinase-active or -deficient isoforms is mediated predominantly through the use of multiple transcription initiation sites (PMID:14645531)
• Three different truncating mutations of HSN2 is associated with hereditary sensory and autonomic neuropathy (PMID:15060842)
• WNK1 selectively binds to and phosphorylates synaptotagmin 2 (Syt2) within its calcium binding C2 domains. Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on a subset of secretory granules in INS-1 cells. (PMID:15350218)
• Screening of hsn2 gene in an HSAN type II Lebanese family showed a 1bp deletion mutation found in a homozygous state in all affected individuals. (PMID:15455397)
• stimulation of KS-WNK1 expression might be an important element of aldosterone-induced Na(+) retention and hypertension (PMID:15583131)
• WNK kinase may be able to influence ion homeostasis through its effects on synaptotagmin function (review) (PMID:15686619)
• WNK1 is activated by hypertonic stress. WNK1 phosphorylated both WNK4 and WNK2. In addition, the WNK1 autoinhibitory domain inhibited the catalytic activity of these WNKs. (PMID:15883153)
• Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability. (PMID:15911806)
• Polymorphisms in genes regulating renal sodium transport, in particular WNK1, predict interindividual differences in antihypertensive responses to hydrochlorothiazide. (PMID:16172412)
• The kidney-specific WNK1 isoform suppresses thiazide-sensitive Na-Cl cotransport through the inhibition of full length WNK1 activity. (PMID:16204408)
• WNK1 and SPAK/OSR1 mediate the hypotonic stress signaling pathway to cation-chloride-coupled cotransporters (PMID:16263722)
• role of WNK1 in blood pressure regulation; interactions of functional variants of WNK1 with dietary intake or with response to antihypertensive drugs, and their impact on cardiovascular morbidity and mortality (PMID:16301342)
• data indicate that transient receptor potential channel 4(TRPV4) is functionally regulated by WNK family kinases 1 and 4 at the level of cell surface expression (PMID:16403833)
• ROMK is antagonistically regulated by long and kidney-specific WNK1 isoforms (PMID:16428287)
• HSN2 mutations are associated with an early childhood onset of a predominantly sensory neuropathy. (PMID:16534117)
• data establish that the CCT domain functions as a multipurpose docking site, enabling SPAK/OSR1 to interact with substrates (NKCC1) and activators (WNK1/WNK4) (PMID:16669787)
• WNK1 and WNK4 gene products and their regulatory effects suggest an essential role for WNKs in coordinating renal Na-Cl reabsorption and K(+) secretion. (PMID:16820787)
• odd-skipped related 1 and sterile20-related, proline-, alanine-rich kinase are likely links between WNK1 and solute carrier family 12 in a pathway that contributes to volume regulation and blood pressure homeostasis in mammals (PMID:16832045)
• WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 (PMID:16949040)
• These observations shed light on the mechanism by which WNK1 is regulated by hyperosmotic stress. (PMID:17190791)
• molecular mechanism for stimulation of endocytosis of ROMK1 by WNK kinases (PMID:17380208)
• WNK1 is a dual modulator of TGFbeta-Smad signaling pathways (PMID:17392271)
• WNK1 might mediate renal Na(+) retention and hypertension in K(+) deficiency (PMID:17957199)
• HSN2 is a nervous system-specific exon of the WNK1 gene (WNK1/HSN2 isoform). (PMID:18521183)
• Multiple intra- and/or intermolecular interactions of WNK1 domains are at play for regulation of ROMK1 by WNK1 in the kidney. (PMID:18550644)
• Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. (PMID:18591455)
• WNK1 variants on blood pressure are mediated via effects on the gradient of blood pressure change with age. (PMID:18809789)
• intron 1 deletion resulted in the overexpression of long- and kidney specific-WNK1 in the distal convoluted tubule and ubiquitous ectopic KS-WNK1 expression (PMID:18955660)
• Coexpression with active Akt1 increased the phosphorylation of Ser397 and thereby SGK1 kinase activity. SGK1 activation was further augmented by coexpression with the protein kinase WNK1 (with no lysine kinase 1). (PMID:19068477)
• This study demonstrates that the carriers of a recessive mutation for HSAN2 display greater sensitivity to innocuous thermal stimuli, as well as for cold pain, suggesting a possible environmental adaptive advantage of the heterozygous state. (PMID:19228968)
• KS-WNK1 is an important physiological regulator of renal K(+) excretion, likely through its effects on the ROMK1 channel. (PMID:19244242)
• data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH (PMID:19347040)
• Single nucleotide polymorphism in the HSN2 exon of this protein cause hereditary sensory neuropathy type II. (PMID:19361385)
• WNK1 is a novel signaling molecule involved in regulation of LINGO-1 mediated inhibition of neurite extension. (PMID:19363035)
• Variations in the WNK1 gene modulates the effect of dietary intake of sodium and potassium on blood pressure determination. (PMID:19609280)
• Double-reciprocal plots of the initial rates versus the concentration of the substrate revealed that the random sequential activity of WNK catalyzed OXSR1 (oxidative stress response kinase-1) phosphorylation. (PMID:19739668)
• WNK1 promotes cell surface expression of glucose transporter GLUT1 by regulating a Tre-2/USP6-BUB2-Cdc16 domain family member 4 (TBC1D4)-Rab8A complex (PMID:20937822)
• Data show that a large percentage of WNK1 knockdown cells fail to complete cell division, displaying defects in mitotic spindles and also in abscission and cell survival. (PMID:21220314)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	wnk1b	ENSDARG00000039392
danio_rerio	wnk1a	ENSDARG00000078992
mus_musculus	Wnk1	ENSMUSG00000045962
rattus_norvegicus	Wnk1	ENSRNOG00000009956
drosophila_melanogaster	Madm	FBGN0027497
drosophila_melanogaster	Wnk	FBGN0037098
caenorhabditis_elegans		WBGENE00006941
caenorhabditis_elegans	hpo-11	WBGENE00010427

Paralogs (6): NRBP1 (ENSG00000115216), WNK4 (ENSG00000126562), DSTYK (ENSG00000133059), WNK2 (ENSG00000165238), NRBP2 (ENSG00000185189), WNK3 (ENSG00000196632)

Protein

Protein identifiers

Serine/threonine-protein kinase WNK1 — Q9H4A3 (reviewed: Q9H4A3)

Alternative names: Erythrocyte 65 kDa protein, Kinase deficient protein, Protein kinase lysine-deficient 1, Protein kinase with no lysine 1

All UniProt accessions (9): Q9H4A3, A0A6Q8PFM0, F5GWT4, F6UYG0, H0YF81, H0YFP5, H0YH68, H0YH79, I3L251

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx. WNK1 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 WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK, promoting WNK1-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, SLC12A5/KCC2 and 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 SLC12A5/KCC2 and SLC12A6/KCC3 inhibit their activity, blocking ion efflux. Also acts as a regulator of angiogenesis in endothelial cells via activation of OXSR1/OSR1 and STK39/SPAK: activation of OXSR1/OSR1 regulates chemotaxis and invasion, while STK39/SPAK regulates endothelial cell proliferation. Also acts independently of the WNK1-SPAK/OSR1 kinase cascade by catalyzing phosphorylation of other substrates, such as SYT2, PCF11 and NEDD4L. Mediates phosphorylation of SYT2, regulating SYT2 association with phospholipids and membrane-binding. Regulates mRNA export in the nucleus by mediating phosphorylation of PCF11, thereby decreasing the association between PCF11 and POLR2A/RNA polymerase II and promoting mRNA export to the cytoplasm. Acts as a negative regulator of autophagy. Required for the abscission step during mitosis, independently of the WNK1-SPAK/OSR1 kinase cascade. May also play a role in actin cytoskeletal reorganization. Also acts as a scaffold protein independently of its protein kinase activity: negatively regulates cell membrane localization of various transporters and channels, such as SLC4A4, SLC26A6, SLC26A9, TRPV4 and CFTR. Involved in the regulation of epithelial Na(+) channel (ENaC) by promoting activation of SGK1 in a kinase-independent manner: probably acts as a scaffold protein that promotes the recruitment of SGK1 to the mTORC2 complex in response to chloride, leading to mTORC2-dependent phosphorylation and activation of SGK1. Acts as an assembly factor for the ER membrane protein complex independently of its protein kinase activity: associates with EMC2 in the cytoplasm via its amphipathic alpha-helix, and prevents EMC2 ubiquitination and subsequent degradation, thereby promoting EMC2 stabilization. Kinase-defective isoform specifically expressed in kidney, which acts as a dominant-negative regulator of the longer isoform 1. Does not directly inhibit WNK4 and has no direct effect on sodium and chloride ion transport. Down-regulates sodium-chloride cotransporter activity indirectly by inhibiting isoform 1, it associates with isoform 1 and attenuates its kinase activity. In kidney, may play an important role regulating sodium and potassium balance.

Subunit / interactions. Interacts with WNK3. Interacts with WNK4; inhibiting the activity of WNK4. Interacts with SGK1; promoting its activation. Associates with the mTORC2 complex. Interacts with UVRAG. Interacts (via amphipathic alpha-helix region) with EMC2; promoting the ER membrane protein complex assembly. Interacts with isoform 1; inhibiting isoform 1 activity.

Subcellular location. Cytoplasm. Nucleus. Cytoskeleton. Spindle.

Tissue specificity. Widely expressed, with highest levels observed in the testis, heart, kidney and skeletal muscle. Strong expression in dorsal root ganglia and spinal cord. This isoform is kidney-specific and specifically expressed in the distal convoluted tubule (DCT) and connecting tubule (CNT) of the nephron.

Post-translational modifications. Autophosphorylated at Ser-378 and Ser-382, promoting its activity. Autophosphorylation at Ser-382 is inhibited by intracellular calcium. Phosphorylation at Thr-60 increases ability to activate SGK1. Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation. Also ubiquitinated by the BCR(KLHL2) complex. May be O-glycosylated.

Disease relevance. Pseudohypoaldosteronism 2C (PHA2C) [MIM:614492] An autosomal dominant disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, mild hyperchloremic metabolic acidosis in some cases, and correction of physiologic abnormalities by thiazide diuretics. The disease is caused by variants affecting the gene represented in this entry. Neuropathy, hereditary sensory and autonomic, 2A (HSAN2A) [MIM:201300] A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN2A is an autosomal recessive disorder characterized by impairment of pain, temperature and touch sensation, onset of symptoms in infancy or early childhood, occurrence of distal extremity pathologies (paronychia, whitlows, ulcers, and Charcot joints), frequent amputations, sensory loss that affects all modalities of sensation (lower and upper limbs and perhaps the trunk as well), absence or diminution of tendon reflexes (usually in all limbs), minimal autonomic dysfunction, absence of sensory nerve action potentials, and virtual absence of myelinated fibers with decreased numbers of unmyelinated fibers in sural nerves. 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 WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK. Activation requires autophosphorylation of Ser-382 and, to a lower extent, Ser-378. Autophosphorylation and subsequent activation is inhibited by increases in intracellular ionic strength: Cl(-) potently inhibits WNK1 kinase activity via direct binding. Also inhibited by K(+) ions. Inhibited by small compounds staurosporine, tyrphostin 47, as well as Src tyrosine kinase inhibitors PP1 and PP2.

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. The RFXV motifs mediate recognition with downstream kinases OXSR1/OSR1 and STK39/SPAK.

Miscellaneous. Contains the nervous system-specific exon HSN2. Produced by alternative splicing. Contains the nervous system-specific exon HSN2. Produced by alternative splicing. Contains the nervous system-specific exon HSN2. Produced by alternative splicing.

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

Isoforms (6)

UniProt ID	Names	Canonical?
Q9H4A3-1	1, L-WNK1	yes
Q9H4A3-2	2
Q9H4A3-4	3, KS-WNK1, Kidney-Specific
Q9H4A3-5	4, Brain and spinal cord variant
Q9H4A3-6	5, Dorsal root ganglia and sciatic nerve variant, DRG and sciatic nerve variant
Q9H4A3-7	6

RefSeq proteins (4): NP_001171914, NP_055638, NP_061852, NP_998820 (=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 (150 total): compositionally biased region 23, modified residue 21, sequence variant 19, mutagenesis site 18, region of interest 14, strand 14, helix 13, splice variant 8, binding site 7, turn 4, short sequence motif 4, sequence conflict 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6FBK	X-RAY DIFFRACTION	1.74
4PWN	X-RAY DIFFRACTION	1.84
5WE8	X-RAY DIFFRACTION	2.01
5WDY	X-RAY DIFFRACTION	2.46
5TF9	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H4A3-F1	43.93	0.12

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): 368 (proton acceptor)

Ligand- & substrate-binding residues (7): 231; 283; 299; 301–304; 351; 369; 371

Post-translational modifications (21): 15, 19, 60, 167, 174, 378, 382, 1261, 1848, 1978, 2002, 2011, 2012, 2027, 2029, 2032, 2121, 2270, 2286, 2370 …

Mutagenesis-validated functional residues (18):

Position	Phenotype
318	does not affect ability to phosphorylate oxsr1/osr1.
368	abolished serine/threonine-protein kinase activity.
382	decreased autophosphorylation, preventing activation of the serine/threonine-protein kinase activity.
1255	does not affect binding to oxsr1/osr1.
1257	does not affect binding to oxsr1/osr1.
1258	slightly decreased binding to oxsr1/osr1 and stk39/spak; when associated with a-1860. abolished binding to oxsr1/osr1 an
1860	slightly decreased binding to oxsr1/osr1 and stk39/spak; when associated with a-1258. abolished binding to oxsr1/osr1 an
1946	slightly decreased binding to oxsr1/osr1 and stk39/spak; when associated with a-1958. abolished binding to oxsr1/osr1 an
1958	slightly decreased binding to oxsr1/osr1 and stk39/spak; when associated with a-1946. abolished binding to oxsr1/osr1 an
2246	abolished interaction with emc2.
2248	does not affect interaction with emc2.
2249	abolished interaction with emc2.
2250	abolished interaction with emc2.
2251	does not affect interaction with emc2.
2253	abolished interaction with emc2.
2257	abolished interaction with emc2.
2260	does not affect interaction with emc2.
233	abolished serine/threonine-protein kinase activity. does not affect ability to activate sgk1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 631 (showing top): GOBP_MITOTIC_CYTOKINESIS, GOBP_DIGESTION, MODULE_97, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_REGULATION_OF_T_CELL_CHEMOTAXIS, GOBP_NEGATIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, GCM_GSPT1, GOBP_RESPONSE_TO_PEPTIDE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_HETEROTYPIC_CELL_CELL_ADHESION

GO Biological Process (41): regulation of sodium ion transport (GO:0002028), positive regulation of systemic arterial blood pressure (GO:0003084), protein phosphorylation (GO:0006468), monoatomic ion transport (GO:0006811), cell volume homeostasis (GO:0006884), DNA damage response (GO:0006974), signal transduction (GO:0007165), heart development (GO:0007507), negative regulation of autophagy (GO:0010507), negative regulation of sodium ion transport (GO:0010766), regulation of mRNA export from nucleus (GO:0010793), positive regulation of T cell chemotaxis (GO:0010820), intracellular chloride ion homeostasis (GO:0030644), negative regulation of protein ubiquitination (GO:0031397), negative regulation of cell-cell adhesion mediated by integrin (GO:0033633), negative regulation of heterotypic cell-cell adhesion (GO:0034115), intracellular signal transduction (GO:0035556), sodium ion transmembrane transport (GO:0035725), chemokine (C-C motif) ligand 21 signaling pathway (GO:0038116), protein insertion into ER membrane by stop-transfer membrane-anchor sequence (GO:0045050), positive regulation of angiogenesis (GO:0045766), neuron development (GO:0048666), T cell receptor signaling pathway (GO:0050852), negative regulation of small GTPase mediated signal transduction (GO:0051058), potassium ion homeostasis (GO:0055075), monoatomic cation homeostasis (GO:0055080), cellular hyperosmotic response (GO:0071474), negative regulation of pancreatic juice secretion (GO:0090188), positive regulation of canonical Wnt signaling pathway (GO:0090263), lymphocyte migration into lymph node (GO:0097022), membraneless organelle assembly (GO:0140694), regulation of sodium ion transmembrane transport (GO:1902305), negative regulation of leukocyte cell-cell adhesion (GO:1903038), negative regulation of protein localization to plasma membrane (GO:1903077), positive regulation of mitotic cytokinesis (GO:1903490), regulation of monoatomic cation transmembrane transport (GO:1904062), positive regulation of termination of RNA polymerase II transcription (GO:1904595), cellular response to chemokine (GO:1990869), regulation of blood pressure (GO:0008217), homeostatic process (GO:0042592)

GO Molecular Function (12): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein kinase binding (GO:0019901), phosphatase binding (GO:0019902), protein kinase activator activity (GO:0030295), protein serine kinase activity (GO:0106310), molecular condensate scaffold activity (GO:0140693), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), protein-containing complex (GO:0032991), intracellular membraneless organelle (GO:0043232), mitotic spindle (GO:0072686), spindle (GO:0005819), cytoskeleton (GO:0005856)

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
sodium ion transport	3
intracellular anatomical structure	3
protein kinase activity	3
cellular anatomical structure	3
negative regulation of cell-cell adhesion	2
intracellular membraneless organelle	2
regulation of metal ion transport	1
regulation of systemic arterial blood pressure	1
positive regulation of blood pressure	1
phosphorylation	1
protein modification process	1
transport	1
regulation of cell size	1
cellular homeostasis	1
cellular response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
animal organ development	1
circulatory system development	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
regulation of sodium ion transport	1
negative regulation of monoatomic ion transport	1
mRNA export from nucleus	1
regulation of RNA export from nucleus	1
regulation of ribonucleoprotein complex localization	1
T cell chemotaxis	1
regulation of T cell chemotaxis	1
positive regulation of lymphocyte chemotaxis	1
positive regulation of T cell migration	1
intracellular monoatomic anion homeostasis	1
chloride ion homeostasis	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
negative regulation of cell adhesion mediated by integrin	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

161 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
OXSR1	WNK1	psi-mi:“MI:0915”(physical association)	0.830
OXSR1	WNK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.830
OXSR1	WNK1	psi-mi:“MI:0407”(direct interaction)	0.830
WNK1	OXSR1	psi-mi:“MI:0915”(physical association)	0.830
HSPA8	GAK	psi-mi:“MI:0914”(association)	0.760
OPG044	DDX3X	psi-mi:“MI:0914”(association)	0.730
YWHAE	WNK1	psi-mi:“MI:0915”(physical association)	0.710
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
STAMBPL1	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
TSC22D4	TSC22D2	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
WNK1	PPP1CA	psi-mi:“MI:0915”(physical association)	0.540
PPP1CA	WNK1	psi-mi:“MI:0407”(direct interaction)	0.540
WNK1	PLEC	psi-mi:“MI:0915”(physical association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
METTL6	TYW5	psi-mi:“MI:0914”(association)	0.530
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
CHCHD4	ENSA	psi-mi:“MI:0914”(association)	0.530

BioGRID (210): WNK1 (Two-hybrid), WNK1 (Biochemical Activity), WNK1 (Biochemical Activity), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), WNK1 (Proximity Label-MS), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS), WNK1 (Affinity Capture-MS)

ESM2 similar proteins: A2ASS6, A8DYP0, E9QMW4, G4SLH0, J7M799, M9MRD1, O15061, O43491, O55103, O70318, O75952, O77788, P07197, P08553, P08855, P11799, P12839, P16053, P27321, P51125, P54938, P57786, P82179, P83741, Q06637, Q13061, Q23551, Q28820, Q4R3X7, Q63425, Q66H38, Q696W0, Q6TS35, Q70IV5, Q7Z589, Q7ZUV7, Q86TC9, Q8BMB0, Q8TC56, Q8WZ42

Diamond homologs: A0A509AKL0, A1Z9X0, A2CI34, A2CI35, A5K0N4, O73792, P00537, P00538, P00540, P04409, P05128, P05129, P05696, P06245, P09215, P0CD62, P10102, P16879, P17252, P20444, P28582, P28867, P32593, P43298, P63318, P63319, P83099, P83741, P93050, P93759, Q02111, Q04759, Q05655, Q12469, Q1L6Q1, Q20CR4, Q2MHE4, Q38868, Q38872, Q38873

SIGNOR signaling

24 interactions.

A	Effect	B	Mechanism
AKT	up-regulates	WNK1	phosphorylation
WNK1	up-regulates	OXSR1	phosphorylation
WNK1	up-regulates	STK39	phosphorylation
WNK1	up-regulates	WNK1	phosphorylation
WNK1	down-regulates	SLC12A6	phosphorylation
AKT1	up-regulates	WNK1	phosphorylation
WNK3	“up-regulates activity”	WNK1	phosphorylation
WNK2	“up-regulates activity”	WNK1	phosphorylation
WNK1	“up-regulates activity”	WNK1	phosphorylation
WNK1	“up-regulates activity”	SYT2	phosphorylation
KLHL3	“down-regulates quantity by destabilization”	WNK1	binding
“Cullin 3-RBX1-Skp1”	“down-regulates quantity by destabilization”	WNK1	ubiquitination
KLHL2	“down-regulates quantity by destabilization”	WNK1	binding
“Cullin 3-RBX1-Skp1”	“down-regulates quantity by destabilization”	WNK1	polyubiquitination
WNK1	“up-regulates activity”	SLC12A2	phosphorylation
WNK1	“down-regulates activity”	SLC12A5	phosphorylation
WNK1	“up-regulates quantity”	SMAD2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 146 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	9	63.4×	2e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	43.5×	9e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	43.5×	9e-09
Activation of BH3-only proteins	9	41.4×	8e-11
Intrinsic Pathway for Apoptosis	9	24.4×	9e-09
RHO GTPases activate PKNs	8	23.5×	1e-07
Signaling by RAS mutants	5	19.6×	1e-04
FOXO-mediated transcription	6	18.7×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of innate immune response	5	19.2×	3e-03
protein targeting	5	13.8×	7e-03
intracellular protein localization	9	7.1×	3e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

2369 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	16
Uncertain significance	1307
Likely benign	690
Benign	120

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069964	NM_213655.5(WNK1):c.2436C>A (p.Tyr812Ter)	Pathogenic
1071299	NM_213655.5(WNK1):c.2462_2463dup (p.Ile822fs)	Pathogenic
1075747	NM_213655.5(WNK1):c.3088_3091del (p.Val1030fs)	Pathogenic
1393975	NM_213655.5(WNK1):c.3373C>T (p.Gln1125Ter)	Pathogenic
1452033	NM_213655.5(WNK1):c.3096del (p.Pro1033fs)	Pathogenic
1452138	NM_213655.5(WNK1):c.3535C>T (p.Gln1179Ter)	Pathogenic
1690362	NM_213655.5(WNK1):c.3238dup (p.Val1080fs)	Pathogenic
1729654	NM_213655.5(WNK1):c.3274C>T (p.Gln1092Ter)	Pathogenic
1794570	NM_213655.5(WNK1):c.2673_2674del (p.Ala891_Ser892insTer)	Pathogenic
1998479	NM_213655.5(WNK1):c.2446_2449del (p.Gln816fs)	Pathogenic
2030440	NM_018979.4(WNK1):c.5267dup (p.Thr1757fs)	Pathogenic
2107370	NM_213655.5(WNK1):c.3086_3087del (p.Pro1029fs)	Pathogenic
21269	NM_213655.5(WNK1):c.2952del (p.Glu984fs)	Pathogenic
21270	NM_213655.5(WNK1):c.3276dup (p.Ser1093fs)	Pathogenic
2128894	NM_213655.5(WNK1):c.3209T>A (p.Leu1070Ter)	Pathogenic
2137282	NM_213655.5(WNK1):c.2998del (p.Arg1000fs)	Pathogenic
2165720	NM_018979.4(WNK1):c.2266C>T (p.Gln756Ter)	Pathogenic
2921775	NM_018979.4(WNK1):c.3962_3963del (p.Thr1321fs)	Pathogenic
2936837	NM_213655.5(WNK1):c.2739_2740del (p.Tyr913_Ser914delinsTer)	Pathogenic
2939328	NM_213655.5(WNK1):c.3438del (p.Ser1147fs)	Pathogenic
2942898	NM_018979.4(WNK1):c.5270_5273del (p.Thr1757fs)	Pathogenic
3244327	NC_000012.11:g.(?862732)(1017958_?)del	Pathogenic
3752782	NM_018979.4(WNK1):c.6376C>T (p.Arg2126Ter)	Pathogenic
3755640	NM_018979.4(WNK1):c.4847_4848insTA (p.Leu1617fs)	Pathogenic
3755789	NM_018979.4(WNK1):c.6426del (p.Asn2143fs)	Pathogenic
3759516	NM_213655.5(WNK1):c.2497_2503del (p.Pro833fs)	Pathogenic
4784152	NM_213655.5(WNK1):c.2694_2695del (p.Ser898_Cys899insTer)	Pathogenic
4786469	NM_213655.5(WNK1):c.3627_3630del (p.Pro1210fs)	Pathogenic
5161	NM_213655.4(WNK1):c.759+12272_760-5774del	Pathogenic
5162	nsv513769	Pathogenic

SpliceAI

4822 predictions. Top by Δscore:

Variant	Effect	Δscore
12:762577:TAGA:T	donor_gain	1.0000
12:762578:AGAA:A	donor_gain	1.0000
12:762585:AGAG:A	donor_gain	1.0000
12:813633:T:TA	acceptor_gain	1.0000
12:813640:A:AG	acceptor_gain	1.0000
12:813640:AG:A	acceptor_gain	1.0000
12:813640:AGG:A	acceptor_loss	1.0000
12:813641:G:A	acceptor_loss	1.0000
12:813641:G:GT	acceptor_gain	1.0000
12:813641:GG:G	acceptor_gain	1.0000
12:813812:AAC:A	donor_gain	1.0000
12:813813:AC:A	donor_gain	1.0000
12:813815:G:GG	donor_gain	1.0000
12:827026:ACTTT:A	acceptor_gain	1.0000
12:827040:A:AG	acceptor_gain	1.0000
12:827040:AG:A	acceptor_gain	1.0000
12:827041:G:GG	acceptor_gain	1.0000
12:827041:GG:G	acceptor_gain	1.0000
12:827041:GGT:G	acceptor_gain	1.0000
12:827041:GGTA:G	acceptor_gain	1.0000
12:827041:GGTAT:G	acceptor_gain	1.0000
12:827259:ATAG:A	donor_gain	1.0000
12:827263:G:C	donor_loss	1.0000
12:827263:G:GG	donor_gain	1.0000
12:827264:T:G	donor_loss	1.0000
12:830156:CCAGT:C	donor_gain	1.0000
12:830157:CAGT:C	donor_gain	1.0000
12:830158:AGTGT:A	donor_loss	1.0000
12:830159:GT:G	donor_gain	1.0000
12:830160:TGTA:T	donor_loss	1.0000

AlphaMissense

15314 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:754224:T:C	F220S	1.000
12:754227:T:C	L221P	1.000
12:754232:T:C	F223L	1.000
12:754233:T:C	F223S	1.000
12:754234:T:A	F223L	1.000
12:754234:T:G	F223L	1.000
12:754260:T:C	F232S	1.000
12:754271:T:G	Y236D	1.000
12:754305:T:A	V247D	1.000
12:754308:C:A	A248D	1.000
12:754310:T:A	W249R	1.000
12:754310:T:C	W249R	1.000
12:754312:G:C	W249C	1.000
12:754312:G:T	W249C	1.000
12:813675:T:C	F265L	1.000
12:813676:T:C	F265S	1.000
12:813677:T:A	F265L	1.000
12:813677:T:G	F265L	1.000
12:813697:T:C	L272S	1.000
12:813730:T:C	F283S	1.000
12:813741:T:A	W287R	1.000
12:813741:T:C	W287R	1.000
12:813775:T:A	V298D	1.000
12:813778:T:C	L299S	1.000
12:813787:A:T	E302V	1.000
12:813790:T:C	L303P	1.000
12:827047:T:C	L313P	1.000
12:827053:G:T	R315M	1.000
12:827055:T:C	F316L	1.000
12:827056:T:C	F316S	1.000

dbSNP variants (sampled 300 via entrez): RS1000026168 (12:831616 CTT>C), RS1000074522 (12:904901 C>T), RS1000091495 (12:833007 A>C,G,T), RS1000106493 (12:786686 C>G,T), RS1000107581 (12:766618 A>T), RS1000121467 (12:853755 G>A), RS1000122860 (12:821584 G>A), RS1000131841 (12:898061 T>C), RS1000134877 (12:808131 G>C), RS1000191334 (12:855044 A>C,G), RS1000217887 (12:851567 G>A), RS1000253112 (12:898407 C>T), RS1000257385 (12:812862 T>A,G), RS1000267462 (12:821896 G>C), RS1000271084 (12:769448 C>A,G,T)

Disease associations

OMIM: gene MIM:605232 | disease phenotypes: MIM:614492, MIM:201300, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
neuropathy, hereditary sensory and autonomic, type 2A	Definitive	Autosomal recessive
pseudohypoaldosteronism type 2C	Strong	Autosomal dominant
hereditary sensory and autonomic neuropathy type 2	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neuropathy, hereditary sensory and autonomic, type 2A	Definitive	AR

Mondo (6): pseudohypoaldosteronism type 2C (MONDO:0013778), neuropathy, hereditary sensory and autonomic, type 2A (MONDO:0024309), hereditary motor and sensory neuropathy (MONDO:0015358), peripheral neuropathy (MONDO:0005244), Charcot-Marie-Tooth disease (MONDO:0015626), hereditary sensory and autonomic neuropathy type 2 (MONDO:0019941)

Orphanet (5): Pseudohypoaldosteronism type 2 (Orphanet:757), Pseudohypoaldosteronism type 2C (Orphanet:88940), Hereditary sensory and autonomic neuropathy type 2 (Orphanet:970), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), OBSOLETE: Hereditary motor and sensory neuropathy (Orphanet:140450)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000224	Hypogeusia
HP:0000762	Decreased nerve conduction velocity
HP:0000822	Hypertension
HP:0000970	Anhidrosis
HP:0000975	Hyperhidrosis
HP:0001069	Episodic hyperhidrosis
HP:0001182	Tapered finger
HP:0001252	Hypotonia
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001810	Dystrophic toenail
HP:0001818	Paronychia
HP:0001842	Foot acroosteolysis
HP:0001939	Abnormality of metabolism/homeostasis
HP:0001942	Metabolic acidosis
HP:0002020	Gastroesophageal reflux
HP:0002153	Hyperkalemia
HP:0002645	Wormian bones
HP:0002661	Painless fractures due to injury
HP:0002797	Osteolysis
HP:0002815	Abnormality of the knee
HP:0003028	Abnormality of the ankle
HP:0003103	Abnormal cortical bone morphology
HP:0003202	Skeletal muscle atrophy
HP:0003272	Abnormal hip bone morphology
HP:0003307	Hyperlordosis
HP:0003351	Decreased circulating renin concentration

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000379_1	Stroke	1.000000e-09
GCST000379_2	Stroke	2.000000e-09
GCST000379_3	Stroke	8.000000e-10
GCST000379_4	Stroke	1.000000e-09
GCST002783_447	Body mass index	2.000000e-07
GCST002783_523	Body mass index	2.000000e-07
GCST002783_89	Body mass index	6.000000e-06
GCST002932_1	Manganese levels	5.000000e-06
GCST004600_5	Eosinophil percentage of white cells	3.000000e-11
GCST004606_68	Eosinophil count	3.000000e-11
GCST004748_25	Lung cancer	6.000000e-12
GCST004749_33	Lung cancer in ever smokers	1.000000e-09
GCST004750_36	Squamous cell lung carcinoma	7.000000e-13
GCST005352_25	Paclitaxel disposition in epithelial ovarian cancer	4.000000e-06
GCST008129_75	Body mass index	5.000000e-15
GCST010988_485	Adult body size	3.000000e-16
GCST010989_34	Body size at age 10	3.000000e-17
GCST90002393_455	Monocyte count	1.000000e-14
GCST90002394_359	Monocyte percentage of white cells	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0009819	comparative body size at age 10, self-reported
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D015417	Hereditary Sensory and Motor Neuropathy	C10.500.300; C10.574.500.495; C10.668.829.800.300; C16.131.666.300; C16.320.400.375
C564162	Pseudohypoaldosteronism, Type IIc (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075173 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs880054	Efficacy	3	hydrochlorothiazide	Hypertension

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs880054	WNK1	3	2.50	1	hydrochlorothiazide
rs1159744	WNK1		0.00	0
rs2107614	WNK1		0.00	0
rs2277869	RAD52, WNK1		0.00	0
rs2286007	WNK1		0.00	0

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
PP1	Inhibition	4.9	pKi

Binding affinities (BindingDB)

2 measured of 4 human assays (4 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
N-(tert-butyl)-1-(1-(5-(5-(trifluoromethyl)-1,3,4-oxadiazol- 2-yl)pyridin-2-yl)piperidin-4-yl)-1H-imidazole-5-carboxamide	IC50	6 nM
(R)-1-(1-(2-(4-methoxyphenyl)acetyl)pyrrolidin-3-yl)-N-phenethyl-1H-imidazole-5-carboxamide (1)	IC50	856 nM

ChEMBL bioactivities

26 potent at pChembl≥5 of 32 total, top 26 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.40	IC50	4	nM	CHEMBL4088706
8.22	IC50	6	nM	CHEMBL4098876
7.49	Ki	32.43	nM	CHEMBL4087727
7.41	IC50	39	nM	CHEMBL4091128
7.22	IC50	60	nM	CHEMBL4065531
7.02	IC50	95	nM	CHEMBL4070177
6.97	IC50	106	nM	CHEMBL4060478
6.92	IC50	120	nM	CHEMBL4100485
6.79	IC50	162	nM	CHEMBL4087727
6.45	EC50	352	nM	CHEMBL4088706
6.38	IC50	420	nM	CHEMBL4100485
6.23	EC50	589	nM	CHEMBL4098876
6.21	IC50	623	nM	CHEMBL4070968
6.12	IC50	750	nM	CHEMBL4083340
6.01	IC50	971	nM	CHEMBL4061509
5.86	EC50	1390	nM	CHEMBL4070177
5.80	IC50	1600	nM	CHEMBL5178104
5.67	IC50	2140	nM	CHEMBL4091817
5.40	IC50	4000	nM	CHEMBL5178104
5.37	IC50	4300	nM	CHEMBL5178104
5.30	IC50	5000	nM	CHEMBL5184443
5.22	IC50	6000	nM	CHEMBL5183064
5.19	IC50	6500	nM	CHEMBL5186592
5.15	Kd	7120	nM	CHEMBL5653589
5.15	ED50	7120	nM	CHEMBL5653589
5.14	IC50	7200	nM	CHEMBL5196892

PubChem BioAssay actives

36 with measured affinity, of 200 total; 21 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
N-tert-butyl-3-[1-[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]piperidin-4-yl]imidazole-4-carboxamide	1802168: In vitro MBP Phosphorylation Assay (MBP) from Article 10.1038/nchembio.2168: “Small-molecule WNK inhibition regulates cardiovascular and renal function.”	ic50	0.0010	uM
[5-chloro-2-[2-(methylamino)-1,3-thiazol-4-yl]-4-pyridinyl]-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]methanone	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.0040	uM
[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-[5-chloro-2-[2-(trideuteriomethylamino)-1,3-thiazol-4-yl]-4-pyridinyl]methanone	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.0060	uM
1-cyclohexyl-N-[[1-[3-(3-methoxyphenyl)phenyl]indol-3-yl]methyl]methanamine	1458705: Non-competitive inhibition of recombinant human N-terminal GST-tagged WNK1 (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate measured every 3 mins from 90 to 250 mins in presence of varying concentration of ATP by Michaelis-Menten plot-based analysis	ki	0.0324	uM
1-cyclohexyl-N-[[6-fluoro-1-[2-(3-methoxyphenyl)-4-pyridinyl]indol-3-yl]methyl]methanamine	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.0390	uM
1-cyclohexyl-N-[[1-[2-(3-methoxyphenyl)-4-pyridinyl]indol-3-yl]methyl]methanamine	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.0600	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	0.0640	uM
N-[[1-[2-(3-methoxyphenyl)-5-methyl-4-pyridinyl]indol-3-yl]methyl]-2-methylpropan-1-amine	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.0950	uM
[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-[2-[2-(methylamino)-1,3-thiazol-4-yl]-4-pyridinyl]methanone	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.1060	uM
(4-benzylpiperazin-1-yl)-[2-(3-methoxyphenyl)quinolin-4-yl]methanone	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.6230	uM
N-[(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl]-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.7500	uM
3-[1-[2-(4-methoxyphenyl)acetyl]pyrrolidin-3-yl]-N-(2-phenylethyl)imidazole-4-carboxamide	1802168: In vitro MBP Phosphorylation Assay (MBP) from Article 10.1038/nchembio.2168: “Small-molecule WNK inhibition regulates cardiovascular and renal function.”	ic50	0.8560	uM
[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-[2-(3-methoxyphenyl)-4-pyridinyl]methanone	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	0.9710	uM
4-[bromo(dichloro)methyl]sulfonyl-N-cyclohexyl-2-nitroaniline	1875492: Inhibition of TEV cleavage site-fused His6-tagged WNK1 (194 to 483 residues) (unknown origin) expressed in Rosetta (DE3) cells using GST-OSR1(314 to 344) peptide as substrate measured after 30 mins by [gamma-32P]-ATP based liquid scintillation counting analysis	ic50	1.6000	uM
1-cyclohexyl-N-[[1-(3-phenylphenyl)indol-3-yl]methyl]methanamine	1458697: Allosteric inhibition of recombinant human N-terminal GST-tagged WNK1 catalytic domain (1 to 491 residues) expressed in baculovirus expression system using fluorescein-labeled OSR1 peptide as substrate after 3 hrs by HTRF assay	ic50	2.1400	uM
4-[bromo(dichloro)methyl]sulfonyl-N-(furan-2-ylmethyl)-2-nitroaniline	1875492: Inhibition of TEV cleavage site-fused His6-tagged WNK1 (194 to 483 residues) (unknown origin) expressed in Rosetta (DE3) cells using GST-OSR1(314 to 344) peptide as substrate measured after 30 mins by [gamma-32P]-ATP based liquid scintillation counting analysis	ic50	5.0000	uM
(2-fluorophenyl)-[5-[2-(methylamino)-1,3-thiazol-4-yl]-2,3-dihydroindol-1-yl]methanone	1802279: WNK1 HTRF Assay from Article 10.1021/acschembio.6b00511: “Discovery and Characterization of Allosteric WNK Kinase Inhibitors.”	ic50	5.7000	uM
4-[bromo(dichloro)methyl]sulfonyl-2-nitro-N-(4-phenylbutyl)aniline	1875492: Inhibition of TEV cleavage site-fused His6-tagged WNK1 (194 to 483 residues) (unknown origin) expressed in Rosetta (DE3) cells using GST-OSR1(314 to 344) peptide as substrate measured after 30 mins by [gamma-32P]-ATP based liquid scintillation counting analysis	ic50	6.0000	uM
4-[bromo(dichloro)methyl]sulfonyl-N-cyclopentyl-2-nitroaniline	1875492: Inhibition of TEV cleavage site-fused His6-tagged WNK1 (194 to 483 residues) (unknown origin) expressed in Rosetta (DE3) cells using GST-OSR1(314 to 344) peptide as substrate measured after 30 mins by [gamma-32P]-ATP based liquid scintillation counting analysis	ic50	6.5000	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149784: Binding affinity to human WNK1 incubated for 45 mins by Kinobead based pull down assay	kd	7.1197	uM
4-[bromo(dichloro)methyl]sulfonyl-2-nitro-N-phenylaniline	1875492: Inhibition of TEV cleavage site-fused His6-tagged WNK1 (194 to 483 residues) (unknown origin) expressed in Rosetta (DE3) cells using GST-OSR1(314 to 344) peptide as substrate measured after 30 mins by [gamma-32P]-ATP based liquid scintillation counting analysis	ic50	7.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression	3
bisphenol F	affects cotreatment, increases methylation, decreases expression	2
bisphenol A	affects cotreatment, increases methylation, increases phosphorylation	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Rotenone	decreases expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
nobiletin	decreases reaction, increases expression	1
sodium arsenate	decreases reaction, increases expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	decreases expression, increases abundance	1
coumarin	affects phosphorylation	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Ethanol	increases expression, affects cotreatment	1
Amiodarone	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1

ChEMBL screening assays

165 unique, capped per target: 165 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1105938	Binding	Inhibition of WNK1 at 5 uM	Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1ZK	Abcam A-549 WNK1 KO	Cancer cell line	Male
CVCL_D2DL	Abcam HCT 116 WNK1 KO	Cancer cell line	Male
CVCL_TY05	HAP1 WNK1 (-) 1	Cancer cell line	Male
CVCL_TY06	HAP1 WNK1 (-) 2	Cancer cell line	Male
CVCL_TY07	HAP1 WNK1 (-) 3	Cancer cell line	Male
CVCL_TY08	HAP1 WNK1 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.