CLCNKA

Summary

CLCNKA (chloride voltage-gated channel Ka, HGNC:2026) is a protein-coding gene on chromosome 1p36.13, encoding Chloride channel protein ClC-Ka (P51800). Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.

This gene is a member of the CLC family of voltage-gated chloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit called barttin to form a functional channel. It is thought to function in salt reabsorption in the kidney and potassium recycling in the inner ear. The gene is highly similar to CLCNKB, which is located 10 kb downstream from this gene. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1187 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bartter disease type 4B (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 257 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 50
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004070

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2026
Approved symbol	CLCNKA
Name	chloride voltage-gated channel Ka
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	hClC-Ka, ClC-K1, CLCK1
Ensembl gene	ENSG00000186510
Ensembl biotype	protein_coding
OMIM	602024
Entrez	1187

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 33 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000331433, ENST00000375692, ENST00000439316, ENST00000464764, ENST00000477360, ENST00000491433, ENST00000495784, ENST00000861477, ENST00000861478, ENST00000861479, ENST00000861480, ENST00000861481, ENST00000861482, ENST00000861483, ENST00000861484, ENST00000861485, ENST00000861486, ENST00000861487, ENST00000861488, ENST00000861489, ENST00000861490, ENST00000861491, ENST00000861492, ENST00000861493, ENST00000861494, ENST00000861495, ENST00000861496, ENST00000861497, ENST00000861498, ENST00000861499, ENST00000861500, ENST00000861501, ENST00000861502, ENST00000861503, ENST00000956816, ENST00000956817, ENST00000956818

RefSeq mRNA: 3 — MANE Select: NM_004070 NM_001042704, NM_001257139, NM_004070

CCDS: CCDS167, CCDS41269, CCDS57973

Canonical transcript exons

ENST00000331433 — 20 exons

Exon	Start	End
ENSE00001932203	16022036	16022063
ENSE00003459877	16032203	16032291
ENSE00003476219	16023800	16023928
ENSE00003479226	16029965	16030075
ENSE00003502050	16027821	16027905
ENSE00003504829	16033170	16033256
ENSE00003520542	16027310	16027435
ENSE00003536293	16026697	16026775
ENSE00003537098	16030461	16030674
ENSE00003537928	16026536	16026613
ENSE00003545843	16022613	16022719
ENSE00003551942	16029126	16029299
ENSE00003561533	16033611	16034050
ENSE00003567324	16028761	16028845
ENSE00003580287	16026108	16026247
ENSE00003590126	16031710	16031843
ENSE00003608426	16028018	16028119
ENSE00003609010	16029731	16029800
ENSE00003611681	16032443	16032526
ENSE00003663270	16024763	16024891

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 97.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4773 / max 48.3036, expressed in 91 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
953	0.1981	50
954	0.1065	37
952	0.1038	41
948	0.0241	7
951	0.0201	9
949	0.0160	8
950	0.0087	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	97.84	gold quality
adult mammalian kidney	UBERON:0000082	94.99	gold quality
left lobe of thyroid gland	UBERON:0001120	94.32	gold quality
thyroid gland	UBERON:0002046	93.12	gold quality
right lobe of thyroid gland	UBERON:0001119	92.56	gold quality
kidney	UBERON:0002113	90.08	gold quality
pituitary gland	UBERON:0000007	88.42	gold quality
vastus lateralis	UBERON:0001379	87.22	gold quality
adenohypophysis	UBERON:0002196	85.73	gold quality
cortex of kidney	UBERON:0001225	85.57	gold quality
quadriceps femoris	UBERON:0001377	85.32	gold quality
body of pancreas	UBERON:0001150	78.39	gold quality
right adrenal gland cortex	UBERON:0035827	78.26	gold quality
epithelium of bronchus	UBERON:0002031	77.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.27	silver quality
right hemisphere of cerebellum	UBERON:0014890	77.13	gold quality
cerebellar hemisphere	UBERON:0002245	76.83	gold quality
cerebellar cortex	UBERON:0002129	76.68	gold quality
cerebellum	UBERON:0002037	76.61	gold quality
body of stomach	UBERON:0001161	76.53	gold quality
left adrenal gland cortex	UBERON:0035825	76.24	gold quality
left adrenal gland	UBERON:0001234	75.70	gold quality
right adrenal gland	UBERON:0001233	75.59	gold quality
right testis	UBERON:0004534	75.30	gold quality
left testis	UBERON:0004533	75.28	gold quality
testis	UBERON:0000473	74.57	gold quality
fundus of stomach	UBERON:0001160	74.29	gold quality
adrenal tissue	UBERON:0018303	73.40	gold quality
adrenal gland	UBERON:0002369	73.23	gold quality
stomach	UBERON:0000945	73.06	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	14.03
E-CURD-114	yes	11.16
E-CURD-135	no	889.35
E-ANND-3	no	1.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF15, MAZ

miRNA regulators (miRDB)

16 targeting CLCNKA, 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-4492	99.87	68.25	3611
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-6514-3P	97.52	66.50	808
HSA-MIR-1292-5P	96.74	62.14	238
HSA-MIR-6894-3P	96.73	65.64	798
HSA-MIR-4471	95.11	66.84	755

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• Combined impairment of ClC-Ka and ClC-Kb results in phenotype that mimics neonatal Barrter’s syndrome with deafness (PMID:15044642)
• Barttin modulates trafficking and function of ClC-K1 and ClC-Kb channels (PMID:16849430)
• CLCNKA genetic variants may have roles in salt-sensitive hypertension (PMID:17510212)
• The structure of the cytoplasmic domain of CLCNKA reveals a conserved interaction interface. (PMID:17562318)
• Disruption of the gene encoding Barttin, BSND, results in a ‘double knockout’ of the functions of both ClCKA and ClCKB, manifesting as Bartter syndrome type IV with sensorineural deafness and an especially severe salt-losing phenotype. (PMID:18094726)
• ClC-Ka and ClC-Kb differ in how conformational changes are translated to the extracellular domain, despite the fact that the cytoplasmic domains share the same quaternary structure (PMID:18648499)
• Identify a protein region that is involved in calcium binding and that is likely undergoing conformational changes underlying the complex gating of CLC-K channels. (PMID:20805576)
• The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardio-renal axis. (PMID:21248228)
• following variables were significantly associated with an estimated glomerular filtration rate: age, type 2 diabetes, total cholesterol, LDL-cholesterol, and the CLCNKA GG genotype (PMID:23850580)
• HEK293 cells the potentiating effect of niflumic acid (NFA) on CLC-Ka/barttin and CLC-Kb/barttin channels seems to be absent while the blocking efficacy of niflumic acid and benzofuran derivatives observed in oocytes is preserved (PMID:24863058)
• Single loci of tag Single Nucleotide Polymorphisms of CLCNKA_B are not enough to increase the Essential Hypertension susceptibility, the combination of CLCNKA SNP, salt, marine products, meat, edible oil consumption is associated with elevated risk. (PMID:25919862)
• R8W and G47R, two naturally occurring barttin mutations identified in patients with Bartter syndrome type IV, reduce barttin palmitoylation and CLC-K/barttin channel activity. (PMID:26013830)
• Increasing expression of barttin over that of ClC-K partially recovered this insufficiency, indicating that N-terminal modifications of barttin alter both binding affinities and gating properties (PMID:29674316)
• Role of PKC in the Regulation of the Human Kidney Chloride Channel ClC-Ka. (PMID:32581267)
• Expanding Genotype-Phenotype Correlation of CLCNKA and CLCNKB Variants Linked to Hearing Loss. (PMID:38069401)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Clcnkb	ENSMUSG00000006216
mus_musculus	Clcnka	ENSMUSG00000033770
rattus_norvegicus	Clcnkb	ENSRNOG00000009897
rattus_norvegicus	Clcnka	ENSRNOG00000052368
drosophila_melanogaster	ClC-c	FBGN0036566
drosophila_melanogaster	ClC-a	FBGN0051116
caenorhabditis_elegans		WBGENE00000530
caenorhabditis_elegans		WBGENE00000532

Paralogs (8): CLCN6 (ENSG00000011021), CLCN4 (ENSG00000073464), CLCN7 (ENSG00000103249), CLCN3 (ENSG00000109572), CLCN2 (ENSG00000114859), CLCN5 (ENSG00000171365), CLCNKB (ENSG00000184908), CLCN1 (ENSG00000188037)

Protein

Protein identifiers

Chloride channel protein ClC-Ka — P51800 (reviewed: P51800)

Alternative names: ClC-K1

All UniProt accessions (1): P51800

UniProt curated annotations — full annotation on UniProt →

Function. Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide. Forms a homodimeric channel where each subunit has its own ion conduction pathway. May conduct double-barreled currents controlled by two types of gates, two fast gates that control each subunit independently and a slow common gate that opens and shuts off both subunits simultaneously. Assembles with the regulatory subunit BSND/Barttin for sorting at the basolateral plasma membrane domain and functional switch to the ion conducting state. CLCNKA:BSND channels display mostly a linear current-voltage relationship with fast gating at negative potentials. Mediates transepithelial chloride transport from the lumen to interstitial compartment along the thin ascending limb of Henle’s loop, contributing to generation of hypertonic medullary interstitium as a countercurrent system to achieve urine concentration. Conducts chloride currents in the stria vascularis of the inner ear to establish the endocochlear potential necessary for normal hearing.

Subunit / interactions. Homodimer. Interacts with BSND.

Subcellular location. Basolateral cell membrane.

Disease relevance. Bartter syndrome 4B, neonatal, with sensorineural deafness (BARTS4B) [MIM:613090] A digenic 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. BARTS4B is associated with sensorineural deafness. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Loss-of-function of both CLCNKA and CLCNKB results in the disease phenotype.

Activity regulation. Activated by extracellular Ca(2+) and inhibited by extracellular acidic pH.

Similarity. Belongs to the chloride channel (TC 2.A.49) family. CLCNKA subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P51800-1	1	yes
P51800-2	2
P51800-3	3

RefSeq proteins (3): NP_001036169, NP_001244068, NP_004061* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000644	CBS_dom	Domain
IPR001807	ClC	Family
IPR002250	Cl_channel-K	Family
IPR014743	Cl-channel_core	Homologous_superfamily
IPR046342	CBS_dom_sf	Homologous_superfamily
IPR050970	Cl_channel_volt-gated	Family

Pfam: PF00571, PF00654

Catalyzed reactions (Rhea), 4 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• nitrate(in) = nitrate(out) (RHEA:34923)
• iodide(out) = iodide(in) (RHEA:66324)
• bromide(in) = bromide(out) (RHEA:75383)

UniProt features (47 total): transmembrane region 10, sequence variant 10, helix 6, binding site 4, mutagenesis site 4, strand 4, domain 2, splice variant 2, sequence conflict 2, chain 1, topological domain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2PFI	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51800-F1	87.10	0.58

Functional residue map

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

Ligand- & substrate-binding residues (4): 259; 261; 278; 281

Mutagenesis-validated functional residues (4):

Position	Phenotype
259	ca(2+)-insensitive.
261	ca(2+)-insensitive.
278	ca(2+)-insensitive.
281	ca(2+)-insensitive.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 185 (showing top): MODULE_416, MODULE_45, MODULE_64, GOBP_INORGANIC_ANION_TRANSPORT, MODULE_16, GOBP_CHLORIDE_TRANSPORT, DELYS_THYROID_CANCER_DN, GOBP_TRANSEPITHELIAL_TRANSPORT, HNF4_DR1_Q3, MODULE_157, MODULE_88, MODULE_396, GOBP_RENAL_ABSORPTION, GOBP_TRANSMEMBRANE_TRANSPORT, SHEN_SMARCA2_TARGETS_DN

GO Biological Process (7): chloride transport (GO:0006821), transepithelial chloride transport (GO:0030321), renal absorption (GO:0070293), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), chloride transmembrane transport (GO:1902476)

GO Molecular Function (6): voltage-gated chloride channel activity (GO:0005247), chloride channel activity (GO:0005254), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), chloride transmembrane transporter activity (GO:0015108)

GO Cellular Component (4): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), chloride channel complex (GO:0034707), membrane (GO:0016020)

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
chloride transport	2
transport	2
monoatomic anion transport	1
inorganic anion transport	1
transepithelial transport	1
renal system process	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
monoatomic anion transmembrane transport	1
chloride channel activity	1
voltage-gated monoatomic anion channel activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
protein binding	1
cation binding	1
binding	1
monoatomic anion transmembrane transporter activity	1
chloride transmembrane transport	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
monoatomic ion channel complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

697 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCNKA	BSND	Q8WZ55	992
CLCNKA	SLC12A1	Q13621	898
CLCNKA	SLC12A3	P55017	872
CLCNKA	KCNJ1	P48048	826
CLCNKA	KLF15	Q9UIH9	793
CLCNKA	AQP2	P41181	779
CLCNKA	MAZ	P56270	664
CLCNKA	SLC9A1	P19634	614
CLCNKA	SLC14A2	Q15849	607
CLCNKA	AVPR2	P30518	597
CLCNKA	HSPB7	Q9UBY9	582
CLCNKA	MAGED2	Q9UNF1	472
CLCNKA	ATP1A1	P05023	440
CLCNKA	ATP1A4	Q13733	433
CLCNKA	KCNJ10	P78508	432

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CLCNKA	CLCNKA	psi-mi:“MI:0407”(direct interaction)	0.560

BioGRID (24): CLCNKA (Biochemical Activity), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), CLCNKA (Two-hybrid), KRTAP21-2 (Two-hybrid)

ESM2 similar proteins: A2BFP5, D3ZJ25, F1NXU8, G3V8V5, O35454, O88454, O97704, P35525, P51788, P51789, P51797, P51800, P51801, P51802, P51803, P51804, P51912, Q06393, Q06495, Q06496, Q1HAQ0, Q28620, Q3SWT5, Q3TD49, Q3TFD2, Q49SH1, Q5PQL3, Q60825, Q62052, Q6AXS0, Q6J4K2, Q71RS6, Q7TN37, Q80SU6, Q8C261, Q8K4R8, Q8N130, Q8NF37, Q8R1P5, Q921R8

Diamond homologs: A1A7K1, A4TPW7, A5F0D5, A6T4V9, A7FM08, A7MGR4, A7N6K9, A7ZHP7, A7ZM51, A7ZWA3, A8ALD3, A9MPK6, A9N0Q1, A9R1E4, B1IQI5, B1IQZ8, B1JK21, B1LEU5, B1LGV8, B1XD25, B1XF57, B2K549, B2U1Q2, B2U300, B4SUY5, B4TK31, B4TXQ7, B5BL83, B5F8R6, B5FHR3, B5FJ02, B5R3G7, B5RHE1, B5Y1L4, B5Z0D5, B5Z428, B6HZD1, B7L5E4, B7LGL7, B7LWB6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	116
Likely benign	43
Benign	78

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
7589	NM_004070.4(CLCNKA):c.240G>C (p.Trp80Cys)	Pathogenic
2582354	NM_004070.4(CLCNKA):c.1885G>T (p.Glu629Ter)	Likely pathogenic

SpliceAI

3523 predictions. Top by Δscore:

Variant	Effect	Δscore
1:16026100:T:A	acceptor_gain	1.0000
1:16026245:GTG:G	donor_gain	1.0000
1:16026530:CTGCA:C	acceptor_loss	1.0000
1:16026531:TGCAG:T	acceptor_loss	1.0000
1:16026532:GCAGG:G	acceptor_loss	1.0000
1:16026533:CA:C	acceptor_loss	1.0000
1:16026534:A:AG	acceptor_gain	1.0000
1:16026534:AG:A	acceptor_gain	1.0000
1:16026534:AGG:A	acceptor_gain	1.0000
1:16026534:AGGG:A	acceptor_loss	1.0000
1:16026535:G:GA	acceptor_loss	1.0000
1:16026535:G:GG	acceptor_gain	1.0000
1:16026535:GG:G	acceptor_gain	1.0000
1:16026535:GGG:G	acceptor_gain	1.0000
1:16026535:GGGC:G	acceptor_gain	1.0000
1:16026535:GGGCC:G	acceptor_gain	1.0000
1:16026609:CTGAG:C	donor_loss	1.0000
1:16026612:AGGTT:A	donor_loss	1.0000
1:16026773:GCG:G	donor_gain	1.0000
1:16027305:CCCA:C	acceptor_loss	1.0000
1:16027308:A:AG	acceptor_gain	1.0000
1:16027309:G:GG	acceptor_gain	1.0000
1:16027309:GGC:G	acceptor_gain	1.0000
1:16027309:GGCGT:G	acceptor_gain	1.0000
1:16027431:GCAGG:G	donor_gain	1.0000
1:16027433:AGGGT:A	donor_loss	1.0000
1:16027434:GG:G	donor_gain	1.0000
1:16027435:G:GT	donor_gain	1.0000
1:16027435:GG:G	donor_loss	1.0000
1:16027436:G:GG	donor_gain	1.0000

AlphaMissense

4446 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:16030478:G:T	G476W	0.996
1:16028029:G:A	G293D	0.991
1:16030479:G:A	G476E	0.991
1:16026772:A:C	S218R	0.990
1:16026774:C:A	S218R	0.990
1:16026774:C:G	S218R	0.990
1:16027321:A:C	S223R	0.990
1:16027323:C:A	S223R	0.990
1:16027323:C:G	S223R	0.990
1:16028037:A:C	S296R	0.990
1:16028039:C:A	S296R	0.990
1:16028039:C:G	S296R	0.990
1:16030470:C:A	A473D	0.990
1:16030574:G:C	A508P	0.988
1:16030464:C:A	A471D	0.987
1:16029980:G:C	R438P	0.986
1:16030478:G:A	G476R	0.986
1:16030478:G:C	G476R	0.986
1:16024819:T:A	W96R	0.985
1:16024819:T:C	W96R	0.985
1:16026198:G:A	G150D	0.985
1:16029979:C:A	R438S	0.985
1:16030463:G:C	A471P	0.985
1:16030467:C:A	A472E	0.985
1:16030575:C:A	A508D	0.985
1:16026197:G:C	G150R	0.984
1:16026206:T:C	C153R	0.984
1:16030067:C:A	A467D	0.984
1:16030469:G:C	A473P	0.984
1:16030481:G:C	A477P	0.984

dbSNP variants (sampled 300 via entrez): RS1000504668 (1:16020106 A>G), RS1001042144 (1:16024913 C>G), RS1001154650 (1:16025228 T>C), RS1001276761 (1:16024345 T>C), RS1001633867 (1:16033488 A>G), RS1002169783 (1:16029191 C>T), RS1002231758 (1:16025915 C>A,T), RS1002284067 (1:16025560 T>C), RS1002771166 (1:16030254 C>G,T), RS1002801855 (1:16020150 A>T), RS1003228481 (1:16026924 C>A,G), RS1003392340 (1:16021676 C>A), RS1003746312 (1:16021953 G>A), RS1003820474 (1:16030852 T>A), RS1003934726 (1:16030494 C>G,T)

Disease associations

OMIM: gene MIM:602024 | disease phenotypes: MIM:613090, MIM:220290, MIM:607197, MIM:607364

GenCC curated gene-disease

Disease	Classification	Inheritance
Bartter disease type 4B	Moderate	Unknown
Bartter syndrome type 4	Supportive	Autosomal recessive

Mondo (5): Bartter disease type 4B (MONDO:0000909), Bartter syndrome type 4 (MONDO:0019524), hearing loss, autosomal recessive (MONDO:0019588), Bartter disease type 3 (MONDO:0011822), sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (5): Bartter syndrome (Orphanet:112), Bartter syndrome type 4 (Orphanet:89938), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Bartter syndrome type 3 (Orphanet:93605)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000083	Renal insufficiency
HP:0000103	Polyuria
HP:0000121	Nephrocalcinosis
HP:0000127	Renal salt wasting
HP:0000325	Triangular face
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000712	Emotional lability
HP:0000822	Hypertension
HP:0000841	Hyperactive renin-angiotensin system
HP:0000848	Increased circulating renin concentration
HP:0000859	Increased circulating aldosterone concentration
HP:0000969	Edema
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001525	Severe failure to thrive
HP:0001561	Polyhydramnios
HP:0001563	Fetal polyuria
HP:0001622	Premature birth
HP:0001919	Acute kidney injury
HP:0001944	Dehydration
HP:0001960	Hypokalemic metabolic alkalosis
HP:0002013	Vomiting
HP:0002150	Hypercalciuria

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST008161_65	Waist circumference adjusted for body mass index	6.000000e-06
GCST010125_4	Left ventricular ejection fraction	6.000000e-25
GCST010796_4092	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-17
GCST010796_4093	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-13
GCST010796_4094	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-20
GCST011198_3	Left ventricular end-systolic volume	1.000000e-12
GCST011206_1	Left ventricular end-diastolic volume	7.000000e-06
GCST011209_1	Left ventricular ejection fraction	2.000000e-10
GCST011216_1	Left ventricular global radial strain	8.000000e-07
GCST011217_1	Left ventricular global circumferential strain	7.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0008373	left ventricular ejection fraction measurement
EFO:0004327	electrocardiography
EFO:0008206	left ventricular systolic function measurement
EFO:0008204	left ventricular diastolic function measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564609	Deafness, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — ClC family

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

Ligand	Action	Affinity	Parameter
niflumic acid	Activator	5.0	pEC50

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methyleugenol	decreases expression	1
VX-agent	increases expression	1
tamibarotene	decreases expression	1
Decitabine	affects expression	1
Zoledronic Acid	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects expression	1
Estradiol	affects binding, increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YA40	IDG-HEK293T-CLCNKA-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT00023036	Not specified	COMPLETED	Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts
NCT00023049	Not specified	COMPLETED	Genetic Analysis of Hereditary Disorders of Hearing and Balance
NCT00261768	Not specified	COMPLETED	Efficacy of Digital Noise Reduction Strategies: A Hearing Aid Trial
NCT00589511	Not specified	COMPLETED	Nucleus Freedom Cochlear Implant System Pediatric Post-approval Study
NCT00678899	Not specified	COMPLETED	Evaluation of the Nucleus Hybrid™ L24 Cochlear Implant System
NCT00787189	Not specified	COMPLETED	Study of Low Level Laser Therapy and Word Recognition in Hearing Impaired Individuals
NCT01184248	Not specified	COMPLETED	The Effect of Sound Stimulation on Pure-tone Hearing Threshold
NCT01434446	Not specified	COMPLETED	The Effect of Sound Stimulation on Hearing Ability
NCT01749592	Not specified	COMPLETED	Single-sided Deafness and Cochlear Implants
NCT01781039	Not specified	COMPLETED	Investigation of Anatomical Correlates of Speech Discrimination
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02093806	Not specified	UNKNOWN	Clinical Applications of Round Window Imaging Anatomy in Cochlear Implant Surgery
NCT02252601	Not specified	UNKNOWN	Evaluation of the High Frequency Digit Triplet Test in Cystic Fibrosis
NCT02584361	Not specified	UNKNOWN	Cochlear Implant and Vestibular Function.
NCT02638883	Not specified	COMPLETED	Implantation of the Cochlear™ Nucleus® Hybrid S Round Window (S-RW) in Adults
NCT02689349	Not specified	COMPLETED	Esteem New Subject Enrollment Post Approval Study
NCT02698787	Not specified	COMPLETED	Fundamental Asynchronous Stimulus Timing Sound Coding Study
NCT02798783	Not specified	COMPLETED	Enlarged Vestibular Aqueduct Registry