WNK4 WNK lysine deficient protein kinase 4 [Homo sapiens (human)] - Gene

Summary

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Official Symbol: WNK4provided by HGNC
Official Full Name: WNK lysine deficient protein kinase 4provided by HGNC
Primary source: HGNC:14544
See related: Ensembl:ENSG00000126562; HPRD:03505; MIM:601844; Vega:OTTHUMG00000180650
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: PHA2B; PRKWNK4
Summary: This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]

Genomic context

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Location :: 17q21-q22

Sequence :: Chromosome: 17; NC_000017.10 (40932649..40949084)

See WNK4 in Epigenomics, MapViewer

Chromosome 17 - NC_000017.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

Bibliography

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GeneRIFs: Gene References Into Functions What's a GeneRIF?

The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction.
Title: The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction.
The Exon 8 G1155942T polymorphism in WNK4 gene was associated with hypertension in the Kazakhs ethnic group in Xinjiang, and the T allele might be the risk factor for essential hypertension.
Title: [Study on the association between genetic polymorphism on WNK4 genes and essential hypertension among Kazakhs ethnic population, in Xinjiang].
R1185C mutation disrupts a CaM binding site at the WNK4 COOH-terminal region and alters the phosphorylation of WNK4 by SGK1.
Title: Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites.
hypertension associated polymorphisms in WNK1 and WNK4 may not be predictors for antihypertensive response to diuretics.
Title: Hypertension associated polymorphisms in WNK1/WNK4 are not associated with hydrochlorothiazide response.
Data show that K1169E lost its inhibitory effect on NCC surface expression compared to wild-type WNK4 when expressed in HEK293 cells, while it did not change NCC total protein expression.
Title: Identification of a novel WNK4 mutation in Chinese patients with pseudohypoaldosteronism type II.
Results show that Tyr512 phosphorylation is a novel signal regulating the prevalence of CFTR at the cell surface and that WNK4 and Syk perform an antagonistic role in this process.
Title: Antagonistic regulation of cystic fibrosis transmembrane conductance regulator cell surface expression by protein kinases WNK4 and spleen tyrosine kinase.
WNK4 WT inhibits Maxi K activity by reducing Maxi K protein at the membrane, but the inhibition is not due to an increase in clathrin-mediated endocytosis of Maxi K, but likely due to enhancing its lysosomal degradation.
Title: WNK4 kinase inhibits Maxi K channel activity by a kinase-dependent mechanism.
WNK4 polymorphism rs56116165 is a rare allelic variant that may contribute to a genetic predisposition to osteoporosis
Title: A WNK4 gene variant relates to osteoporosis and not to hypertension in the Portuguese population.
Data show that 17beta-estradiol/ERalpha regulates human WNK4 expression partly through AP-1 binding to the WNK4 promoter.
Title: Estrogen regulation of human with-no-lysine (K) kinase-4 gene expression involves AP-1 transcription factor.
WNK4 kinase negatively regulates the anterograde trafficking of MR through kinase-independent mechanism.
Title: WNK4 kinase negatively regulates the surface expression of muscarinic M3 receptor.

Submit: New GeneRIF Correction See all (38)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Pseudohypoaldosteronism type 2B

MIM: 614491

Genetic Testing Registry

Summary from GeneReviews: Pseudohypoaldosteronism Type II

Pseudohypoaldosteronism type II (PHAII) is characterized by hypertension and hyperkalemia despite normal glomerular filtration rate (GFR). Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is well described.

Diagnosis Testing

The diagnosis is established by the finding of hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels. Molecular genetic testing of WNK4 and WNK1, the only two genes in which mutations are known to cause PHAII, is available clinically.

Genetic Counseling

PHAII is inherited in an autosomal dominant manner. Each child of an individual with PHAII has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known; however, requests for prenatal testing for conditions which (like PHAII) can be treated effectively are not common.

References

PMID: 22073419

Interactions

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Products	Interactant	Other Gene	Source	Pubs	Description
Q96J92	P41182	BCL6	HPRD	PubMed
Q96J92	O95832	CLDN1	HPRD	PubMed
Q96J92	P57739	CLDN2	HPRD	PubMed
Q96J92	O15551	CLDN3	HPRD	PubMed
Q96J92	O14493	CLDN4	HPRD	PubMed
Q96J92	P55017	SLC12A3	HPRD	PubMed
Q96J92	Q9UEW8	STK39	HPRD	PubMed
BioGRID:122421	BioGRID:106710	AKT1	BioGRID	PubMed	Biochemical Activity
BioGRID:122421	BioGRID:107076	BCL6	BioGRID	PubMed	Affinity Capture-MS
BioGRID:122421	BioGRID:114030	CUL3	BioGRID	PubMed	Affinity Capture-Western
BioGRID:122421	BioGRID:109552	HSP90AA1	BioGRID	PubMed	Affinity Capture-Luminescence
BioGRID:122421	BioGRID:117637	KLHL3	BioGRID	PubMed	Affinity Capture-Western; Biochemical Activity
BioGRID:122421	BioGRID:116915	NEDD4L	BioGRID	PubMed	Biochemical Activity
BioGRID:122421	BioGRID:112344	SGK1	BioGRID	PubMed	Affinity Capture-Western; Biochemical Activity
BioGRID:122421	BioGRID:116983	SIRT1	BioGRID	PubMed	Positive Genetic
BioGRID:122421	BioGRID:118159	STK39	BioGRID	PubMed	Two-hybrid
BioGRID:122421	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-Western
BioGRID:122421	BioGRID:116168	YWHAQ	BioGRID	PubMed	Affinity Capture-MS

Pathways from BioSystems

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Ion channel transport, organism-specific biosystem (from REACTOME)
Ion channel transport, organism-specific biosystemIon channels mediate the flow of ions across the plasma membrane of cells. They are integral membrane proteins, typically a multimer of proteins, which, when arranged in the membrane, create a pore f...
Stimuli-sensing channels, organism-specific biosystem (from REACTOME)
Stimuli-sensing channels, organism-specific biosystemIon channels that mediate sensations such as pain, warmth, cold, taste pressure and vision. Channels that mediate these sensations include acid-sensing ion channels (ASICs) (Wang & Xu 2011, Qadri et ...
Transmembrane transport of small molecules, organism-specific biosystem (from REACTOME)
Transmembrane transport of small molecules, organism-specific biosystem
Transmembrane transport of small molecules

General gene information

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Markers

D11S2921 (e-PCR)
- UniSTS:152074

RH45445 (e-PCR)
- UniSTS:59661

D17S1186 (e-PCR)
- UniSTS:149798

RH66580 (e-PCR)
- UniSTS:89400

L18426 (e-PCR)
- UniSTS:34648

D11S3732 (e-PCR)
- UniSTS:152962

RH47257 (e-PCR)
- UniSTS:44990

D7S2800 (e-PCR)
- UniSTS:60903

Genotypes

See WNK4 SNP Geneview Report
See WNK4 SNP Genotype Report
See WNK4 SNP Variation Viewer Report

Homology

Homologs of the WNK4 gene: The WNK4 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, zebrafish, and rice.
Map Viewer (Mouse, Rat)
OrthoDB: The Hierarchical Catalog of Eukaryotic Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
ATP binding	ISS Inferred from Sequence or Structural Similarity more info
protein serine/threonine kinase activity	ISS Inferred from Sequence or Structural Similarity more info

Process	Evidence Code	Pubs
chloride transport	IEA Inferred from Electronic Annotation more info
intracellular protein kinase cascade	ISS Inferred from Sequence or Structural Similarity more info
ion transport	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of pancreatic juice secretion	IEA Inferred from Electronic Annotation more info
protein localization	IEA Inferred from Electronic Annotation more info
protein phosphorylation	ISS Inferred from Sequence or Structural Similarity more info
regulation of cellular process	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
cytoplasm	IEA Inferred from Electronic Annotation more info
tight junction	ISS Inferred from Sequence or Structural Similarity more info

General protein information

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Preferred Names: serine/threonine-protein kinase WNK4

Names: serine/threonine-protein kinase WNK4; protein kinase with no lysine 4; protein kinase lysine-deficient 4

NP_115763.2

EC 2.7.11.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_016227.1 RefSeqGene

Range

5001..21436

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_032387.4 → NP_115763.2 serine/threonine-protein kinase WNK4

Status: REVIEWED

Source sequence(s)

BC136664, BM683764, CA388932

Consensus CDS

CCDS11439.1

UniProtKB/TrEMBL

B0LPI0

UniProtKB/Swiss-Prot

Q96J92

Related

ENSP00000246914, OTTHUMP00000264871, ENST00000246914, OTTHUMT00000452389

Conserved Domains (3) summary

cd00180
Location:180 – 429
Blast Score: 550

PKc; Catalytic domain of Protein Kinases

smart00220
Location:179 – 432
Blast Score: 599

S_TKc; Serine/Threonine protein kinases, catalytic domain

pfam12202
Location:453 – 489
Blast Score: 141

OSR1_C; Oxidative-stress-responsive kinase 1 C terminal

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 104

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p10 Primary Assembly

Genomic

NC_000017.10 Reference GRCh37.p10 Primary Assembly

Range

40932649..40949084

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000149.1 Alternate HuRef

Range

36697144..36713472

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.0

Genomic

NC_018928.1 Alternate CHM1_1.0

Range

41722010..41738445

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	ABBA01006407.1 (15729..25976)	None
genomic	ABBA01006408.1	None
genomic	AC016889.28 (62306..62678)	None
genomic	AC100793.8 (118450..134465)	None
genomic	AMYH01008398.1 (101295..117730)	None
genomic	CH471152.1	EAW60881.1
		EAW60882.1
genomic	EU332870.1	ABY87559.1
mRNA	AF390018.1	AAK91995.1
mRNA	AJ309861.1	CAC32991.1
mRNA	AJ316534.1	CAC48387.1
mRNA	AK096003.1	BAC04669.1
mRNA	AK096052.1	BAC04688.1
mRNA	AK301963.1	BAG63376.1
mRNA	BC136664.1	AAI36665.1
mRNA	BC144356.1	None
mRNA	BM683764.1	None
mRNA	CA388932.1	None