KCNJ1

protein-coding

potassium inwardly rectifying channel subfamily J member 1, the group of Potassium inwardly rectifying channel subfamily J

Gene summary

Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. It is activated by internal ATP and probably plays an important role in potassium homeostasis. The encoded protein has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Mutations in this gene have been associated with antenatal Bartter syndrome, which is characterized by salt wasting, hypokalemic alkalosis, hypercalciuria, and low blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_153766.3

Inheritance

ClinVar variants

P:84U:134B:91

Top phenotype

Bartter syndrome, antenatal, type 2

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr11:128,836,315-128,867,373

External References & Databases

Ensembl (ENSG00000151704)

Transcript & Mutation Effects

hg38 • Region Span ~31.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bartter disease type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009424

Submitter: ClinGen

*KCNJ1* was first reported in relation to autosomal recessive Bartter disease type 2 in 1996 (Simon et al., PMID: 8841184). Bartter syndrome is characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Antenatal Bartter syndrome (type 2) presents with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. 13 variants (missense, in-frame indel, nonsense, and frameshift) that have been reported in 8 probands in 2 publications (PMIDs: 8841184, 19096086) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by experimental evidence (animal models, expression studies, biochemical function, and in vitro functional assays) (PMIDs: 7635463, 9580661, 12086641, 12122007, 24400161). It was demonstrated that decreased potassium channel-PIP2 interactions underlies the molecular mechanism of Bartter syndrome when *KCNJ1* variants are present in patients. Furthermore, *KCNJ1* is normally expressed in the kidney with variation causing disturbed currents across the potassium channel as functionally demonstrated in multiple variants, c.584C>T (p.Ala195Val), c.600C>G (p.Ser200Arg), c.939_942del (p.Glu315fs), and c.601C>T (p.Leu201Phe). Finally, the *KCNJ1* knockout mouse model generated by Lorenz et al., PMID: 12122007, was well cited and recapitulated the reduction of renal salt reabsorption as seen in patients with Bartter disease type 2. In summary, *KCNJ1* is definitively associated with autosomal recessive Bartter disease type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date June 16, 2022 (SOP Version 9).

Bartter disease type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009424

Submitter: Labcorp Genetics (formerly Invitae)

Bartter disease type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009424

Submitter: PanelApp Australia

Bartter disease type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009424

Submitter: Natera

Clinical Genomic Database (CGD)

Bartter syndrome, antenatal, type 2AR

Manifestation: Renal

Intervention: Renal

Rationale: Prenatal therapy has been reported as being beneficial; In infants, specific medications (eg, COX2 inhibitors) have been reported as beneficial; Correction of hypokalemic alkalosis can be beneficial

Refs: 841184; 9002665; 10049979; 10979805

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNJ1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 209

Bartter disease type 2Total: 142

Inborn genetic diseasesTotal: 39

KCNJ1-related disorderTotal: 23

not specifiedTotal: 20

KCNJ1-related disordersTotal: 15

Bartter syndromeTotal: 11

Renal tubulopathiesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153766.3. 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			2 clinvar	83 clinvar		85
missense	8 clinvar	33 clinvar	131 clinvar	8 clinvar		180
nonsense	7 clinvar	9 clinvar				16
start loss						0
frameshift	12 clinvar	15 clinvar	1 clinvar			28
splice donor/acceptor (+/-2bp)						0
Total	27	57	134	91	0	309

Highest pathogenic variant AF is 0.00017413679

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153766.3	RefSeq	NP_722450.1	1	MANE Select
ENST00000392666.6	Ensembl	ENSP00000376434.1	1	MANE Select
NM_000220.6	RefSeq	NP_000211.1	2	Standard
NM_153764.3	RefSeq	NP_722448.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kcnj1a.1	Danio rerio	Structure: heart contraction Quality: increased rate abnormal

Gene / Model

Organism

Observed Phenotype

kcnj1a.1

Danio rerio

Structure: heart contraction

Quality: increased rate

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric acid secretion - Homo sapiens (human)
Aldosterone-regulated sodium reabsorption - Homo sapiens (human)
Diuretics Pathway, Pharmacodynamics
Neuronal System
Potassium transport channels

Biological Process

potassium ion transport
excretion
regulation of ion transmembrane transport
potassium ion import across plasma membrane

Molecular Function

inward rectifier potassium channel activity
ATP binding
phosphatidylinositol-4,5-bisphosphate binding
ATP-activated inward rectifier potassium channel activity

Cellular Component

plasma membrane
voltage-gated potassium channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392664
Coding exons: 2
Length: 31059
Individuals with no LoFs: 125623
Homozygous LoFs: 0
Heterozygous LoFs: 121
Defined: 125744
p: 0.000481

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.277	229	218	1.05	0.0000118	2606
Missense (PolyPhen)		114	112.5	1.0133		1404
Synonymous	0.232	74	76.6	0.966	0.00000390	760
Loss of Function	0.892	8	11.2	0.713	6.51e-7	136

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00012	rare
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.000033	0.000033	rare
Other	0.0026	0.0026	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: In the kidney, probably plays a major role in potassium homeostasis. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This channel is activated by internal ATP and can be blocked by external barium.;
Disease: DISEASE: Bartter syndrome 2, antenatal (BARTS2) [MIM:241200]: A form of Bartter syndrome, an autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. BARTS2 is a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia. {ECO:0000269|PubMed:8841184, ECO:0000269|PubMed:9002665, ECO:0000269|PubMed:9727001}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.241

Intolerance Scores

LoFtool: 0.0329
RVIS EVS: -0.47
RVIS percentile EVS: 23.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.360

Gene Damage Prediction

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