WNK1

protein-coding

WNK lysine deficient protein kinase 1, the group of WNK lysine deficient protein kinases|Protein phosphatase 1 regulatory subunits|Minor histocompatibility antigens

Gene summary

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.[provided by RefSeq, May 2010]

Previous symbols:

PRKWNK1
HSN2

MANE transcript

NM_018979.4

Inheritance

AD, AR

ClinVar variants

P:27U:951B:546

Top phenotype

Pseudohypoaldosteronism, type IIC; Neuropathy, hereditary sensory and autonomic, type IIA

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr12:752,579-911,452

External References & Databases

Ensembl (ENSG00000060237)

Transcript & Mutation Effects

hg38 • Region Span ~158.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pseudohypoaldosteronism type 2CMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013778

Submitter: Ambry Genetics

neuropathy, hereditary sensory and autonomic, type 2ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024309

Submitter: G2P

neuropathy, hereditary sensory and autonomic, type 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024309

Submitter: PanelApp Australia

pseudohypoaldosteronism type 2CSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013778

Submitter: PanelApp Australia

hereditary sensory and autonomic neuropathy type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019941

Submitter: Orphanet

neuropathy, hereditary sensory and autonomic, type 2ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024309

Submitter: ClinGen

WNK1 was first reported in relation to autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSAN2) in 2004 (Lafreniere et al., PMID: 15060842). Patients' symptoms began in infancy and they suffered from loss of touch and pain sensation in the distal limbs, leading to ulcerations and amputation of digits. Of note, this gene has also been implicated in autosomal dominant pseudohypoaldosteronism (PHA) type IIC (OMIM #614492). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, no overlapping phenotypes were identified in WNK1 patients with the two different diseases. The precise molecular mechanism leading to the diseases is still unknown; however, the two phenotypes are caused by mutations in different isoforms. HSAN2 variants affect a neuronal specific isoform and PHA affects a kidney specific isoform. Moreover, HSAN2 is caused by recessive LOF variants and PHA is caused by dominant intronic deletions leading to increased WNK1 expression. Therefore, the following disease entities have been split into two disease entities, HSAN2 (OMIM: 201300) and pseudohypoaudosteronism (OMIM:614492). Five loss-of-function (LOF) variants (nonsense and frameshift) have been reported in five probands with HSAN2 (PMIDs: 15060842, 15911806, 16636245, 30497409), which are included in this curation reaching the maximum score for genetic evidence (12 pts.). The mechanism of pathogenicity appears to be LOF. The gene-disease association is also supported by expression studies (expressed in the dorsal root ganglion), two animal models (drosophila and mouse), and in vitro functional assay (neurite outgrowth induction) [PMIDs:18521183, 36151370, 23300475, 27025876]. In summary, WNK1 is DEFINETIVELY associated with autosomal recessive HSAN2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

neuropathy, hereditary sensory and autonomic, type 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024309

Submitter: Labcorp Genetics (formerly Invitae)

neuropathy, hereditary sensory and autonomic, type 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024309

Submitter: Ambry Genetics

pseudohypoaldosteronism type 2CSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013778

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Pseudohypoaldosteronism, type IIC; Neuropathy, hereditary sensory and autonomic, type IIAAD/AR

Manifestation: Neurologic; Renal

Intervention: Neurologic; Renal

Rationale: Treatment (eg, correction of physiologic abnormalities by thiazide diuretics) can be effective, and measures towards optimizing blood pressure can decrease morbidity and mortality related to potential sequale of hypertension; In Neuropathy, hereditary sensory and autonomic, type IIl, reduced pain sensation may result in injury, as well as result in ulceration/infection, and precautions may be beneficial

Refs: 20323803; 10869238; 11498583; 15060842; 5455397; 15911806; 16946995; 16636245; 16534117; 18521183; 22080857; 22266938; 21768522; 22073419; 22910560; 22934535

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WNK1 variants in ClinVar

13 Conditions Cataloged

Pseudohypoaldosteronism type 2CTotal: 1975

Neuropathy, hereditary sensory and autonomic, type 2ATotal: 1974

not providedTotal: 337

Inborn genetic diseasesTotal: 248

WNK1-related disorderTotal: 192

not specifiedTotal: 148

Charcot-Marie-Tooth diseaseTotal: 5

Variant of unknown significanceTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018979.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			17 clinvar	462 clinvar	5 clinvar	484
missense		2 clinvar	918 clinvar	75 clinvar	3 clinvar	998
nonsense	3 clinvar	1 clinvar	3 clinvar			7
start loss						0
frameshift	8 clinvar	4 clinvar	8 clinvar	1 clinvar		21
splice donor/acceptor (+/-2bp)		9 clinvar	5 clinvar			14
Total	11	16	951	538	8	1524

Highest pathogenic variant AF is 0.00017155835

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 91 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018979.4	RefSeq	NP_061852.3	28	MANE Select
ENST00000315939.11	Ensembl	ENSP00000313059.6	28	MANE Select
NM_001184985.2	RefSeq	NP_001171914.1	28	Standard
NM_014823.3	RefSeq	NP_055638.2	26	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
wnk1a	Danio rerio	Structure: dorsal longitudinal anastomotic vessel Quality: hypoplastic abnormal

Gene / Model

Organism

Observed Phenotype

wnk1a

Danio rerio

Structure: dorsal longitudinal anastomotic vessel

Quality: hypoplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Diuretics Pathway, Pharmacodynamics
Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

regulation of sodium ion transport
positive regulation of systemic arterial blood pressure
protein phosphorylation
ion transport
negative regulation of sodium ion transport

Molecular Function

magnesium ion binding
protein kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding

Cellular Component

cytoplasm
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315939
Coding exons: 28
Length: 158860
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 125748
p: 0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.16	1043	1.26e+3	0.828	0.0000657	15240
Missense (PolyPhen)		238	314.53	0.75667		3966
Synonymous	-0.881	500	476	1.05	0.0000258	5145
Loss of Function	8.82	7	104	0.0672	0.00000640	1130

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.0011	0.0011	notable
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SCNN1A, SCNN1B, SCNN1D and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide- sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4, SLC26A6 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity). {ECO:0000250|UniProtKB:P83741, ECO:0000250|UniProtKB:Q9JIH7, ECO:0000269|PubMed:10660600, ECO:0000269|PubMed:15060842}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:11498583}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:15060842, ECO:0000269|PubMed:15911806, ECO:0000269|PubMed:18521183}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.210

Intolerance Scores

LoFtool: 0.540
RVIS EVS: -1.07
RVIS percentile EVS: 7.35

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.968

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High