BSND

Summary

BSND (barttin CLCNK type accessory subunit beta, HGNC:16512) is a protein-coding gene on chromosome 1p32.3, encoding Barttin (Q8WZ55). Regulatory subunit of anion-selective CLCNKA:BSND and CLCNKB:BSND heteromeric channels involved in basolateral chloride conductance along the nephron to achieve urine concentration and maintain systemic acid-base homeostasis, and in the stria vascularis of the inner ear to estab….

This gene encodes an essential beta subunit for CLC chloride channels. These heteromeric channels localize to basolateral membranes of renal tubules and of potassium-secreting epithelia of the inner ear. Mutations in this gene have been associated with Bartter syndrome with sensorineural deafness.

Source: NCBI Gene 7809 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bartter disease type 4A (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 419 total — 19 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 55
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_057176

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16512
Approved symbol	BSND
Name	barttin CLCNK type accessory subunit beta
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	BART
Ensembl gene	ENSG00000162399
Ensembl biotype	protein_coding
OMIM	606412
Entrez	7809

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000651561

RefSeq mRNA: 1 — MANE Select: NM_057176 NM_057176

CCDS: CCDS602

Canonical transcript exons

ENST00000651561 — 4 exons

Exon	Start	End
ENSE00001139633	55006997	55007272
ENSE00001139640	55005022	55005116
ENSE00001454811	55008214	55017172
ENSE00003843814	54998933	54999363

Expression profiles

Bgee: expression breadth broad, 22 present calls, max score 84.77.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0161 / max 13.1167, expressed in 6 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2972	0.0081	5
2973	0.0080	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	84.77	gold quality
adult mammalian kidney	UBERON:0000082	72.90	gold quality
metanephros cortex	UBERON:0010533	71.61	gold quality
metanephros	UBERON:0000081	70.68	gold quality
quadriceps femoris	UBERON:0001377	70.37	gold quality
tibialis anterior	UBERON:0001385	69.84	silver quality
kidney	UBERON:0002113	69.31	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	69.31	gold quality
vastus lateralis	UBERON:0001379	69.26	gold quality
epithelial cell of pancreas	CL:0000083	67.87	gold quality
deltoid	UBERON:0001476	66.85	gold quality
nasal cavity epithelium	UBERON:0005384	66.68	gold quality
tendon of biceps brachii	UBERON:0008188	66.27	gold quality
oocyte	CL:0000023	65.73	gold quality
buccal mucosa cell	CL:0002336	65.69	gold quality
pancreatic ductal cell	CL:0002079	64.86	silver quality
trabecular bone tissue	UBERON:0002483	64.69	gold quality
biceps brachii	UBERON:0001507	64.67	gold quality
cortex of kidney	UBERON:0001225	63.95	gold quality
upper arm skin	UBERON:0004263	63.93	gold quality
cerebellar vermis	UBERON:0004720	63.87	gold quality
ileal mucosa	UBERON:0000331	62.64	silver quality
myocardium	UBERON:0002349	62.12	gold quality
renal medulla	UBERON:0000362	61.83	silver quality
lateral globus pallidus	UBERON:0002476	61.74	gold quality
cartilage tissue	UBERON:0002418	61.17	gold quality
colonic mucosa	UBERON:0000317	60.73	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	60.09	gold quality
medial globus pallidus	UBERON:0002477	59.88	gold quality
globus pallidus	UBERON:0001875	59.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	236.14
E-ANND-3	yes	4.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting BSND, 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-4715-3P	99.98	66.03	670
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-146B-3P	97.83	65.29	782
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-6795-3P	91.86	63.00	218

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 20)

• The mislocalization of CLC-K2 was identified as the molecular pathogenesis of Bartter syndrome by mutant barttins. (PMID:12761627)
• ClC-Ka/barttin channels are regulated by SGK1 and SGK3, which may thus participate in the regulation of transport in kidney and inner ear. (PMID:15496163)
• A missense, point mutation on gene BSND exon 1, affects the function of the CLC-K/barttin chloride channel and caused Bartter syndrome with sensorineural deafness in two families from Spain. (PMID:16572343)
• Barttin mutations is associated with antenatal Bartter syndrome with sensorineural deafness (PMID:16773427)
• Barttin modulates trafficking and function of ClC-K1 and ClC-Kb channels (PMID:16849430)
• BSND-V43I, a common variant conferring partial loss of function, exhibits significant deviation from equilibrium in the Ghanaian normotensive control population (PMID:17954364)
• 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)
• Bartter syndrome type IV can be caused by various derangements in the function of barttin, likely contributing to the diversity of observed phenotypes. (PMID:18776122)
• Deletion of exons 2-4 in the BSND gene causes severe antenatal Bartter syndrome. (PMID:18843510)
• In a large cohort of ante/neonatal Bartter syndrome, deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. (PMID:19096086)
• Mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. (PMID:19646679)
• The molecular basis of DFNB73 autosomal recessive deafness is reported. (PMID:19646679)
• Case Report: G47R mutation decreases barttin expression, resulting CIC-K location being changed from the basement membrane to the cytoplasm in the tubule and might have varying effects on renal function associated with factors other than this gene. (PMID:21269598)
• BSND, was first modeled, and then, the identified mutation was further analyzed by using different bioinformatics tools. (PMID:21541222)
• 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)
• These results demonstrate that mutations in a cluster of hydrophobic residues within transmembrane domain 1 affect barttin-CLC-K interaction and impair gating modification by the accessory subunit (PMID:26063802)
• results demonstrate that the carboxyl terminus of hClC-Kb is not part of the binding site for barttin, but functionally modifies the interplay with barttin. (PMID:26453302)
• These results suggest that BSND is expressed only in normal salivary glands and oncocytic salivary gland tumors such as Warthin’s tumor and oncocytoma (PMID:28470573)
• 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)
• DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels. (PMID:32184353)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	bsnd	ENSDARG00000086265
mus_musculus	Bsnd	ENSMUSG00000025418
rattus_norvegicus	Bsnd	ENSRNOG00000006543

Protein

Protein identifiers

Barttin — Q8WZ55 (reviewed: Q8WZ55)

All UniProt accessions (2): Q8WZ55, Q5VU50

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of anion-selective CLCNKA:BSND and CLCNKB:BSND heteromeric channels involved in basolateral chloride conductance along the nephron to achieve urine concentration and maintain systemic acid-base homeostasis, and in the stria vascularis of the inner ear to establish the endocochlear potential necessary for normal hearing. Most likely acts as a chaperone that allosterically regulates proper sorting of CLCNKA:BSND and CLCNKB:BSND channels at the basolateral plasma membrane domain and functional switch to ion conducting state. Mediates constitutive opening of channel common gates.

Subunit / interactions. Interacts with CLCNK channels. Forms heteromers with CLCNKA in the thin ascending limb of Henle and with CLCNKB in the thick ascending limb and more distal segments.

Subcellular location. Basolateral cell membrane.

Tissue specificity. Expressed primarily in kidney. Expressed in specific nephron segments and in the stria vascularis of the inner ear.

Post-translational modifications. Palmitoylation is necessary for activation of plasma membrane-inserted CLC-K/barttin channels.

Disease relevance. Bartter syndrome 4A, neonatal, with sensorineural deafness (BARTS4A) [MIM:602522] 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. BARTS4A is associated with sensorineural deafness. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_476517* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029181	Barttin	Family

Pfam: PF15462

UniProt features (34 total): mutagenesis site 10, sequence variant 9, topological domain 3, region of interest 3, compositionally biased region 2, modified residue 2, lipid moiety-binding region 2, transmembrane region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WZ55-F1	53.80	0.00

Functional residue map

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

Post-translational modifications (4): 110, 168, 54, 56

Mutagenesis-validated functional residues (10):

Position	Phenotype
54–320	abolishes clcnkb channel conductance.
54	38% reduction in palmitoylation. abolishes palmitoylation; when associated with s-56.
56	74% reduction in palmitoylation. abolishes palmitoylation; when associated with s-54.
57–320	abolishes clcnkb channel conductance.
61–320	abolishes clcnkb channel conductance.
72–320	decreases the amplitude of clcnkb channel current but does not affect the open probability.
85–320	decreases the amplitude of clcnkb channel current but does not affect the open probability.
98	stimulation of clcnka and clcnkb currents enhanced; intense localization in the plasma membrane with no intracellular lo
115–320	no effect on clcnkb channel conductance.
243–320	no effect on clcnkb channel conductance.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 158 (showing top): GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, ATF1_Q6, TGACATY_UNKNOWN, GOBP_SENSORY_PERCEPTION, GOBP_TRANSMEMBRANE_TRANSPORT, RAAGNYNNCTTY_UNKNOWN, GOCC_PLASMA_MEMBRANE_REGION, GOCC_BASAL_PART_OF_CELL, GOMF_PASSIVE_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MONOATOMIC_ANION_CHANNEL_ACTIVITY, GOMF_MONOATOMIC_ANION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_CHLORIDE_CHANNEL_REGULATOR_ACTIVITY

GO Biological Process (3): chloride transport (GO:0006821), sensory perception of sound (GO:0007605), chloride transmembrane transport (GO:1902476)

GO Molecular Function (3): chloride channel activity (GO:0005254), chloride channel regulator activity (GO:0017081), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), protein-containing complex (GO:0032991), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic anion transport	1
inorganic anion transport	1
sensory perception of mechanical stimulus	1
chloride transport	1
monoatomic anion transmembrane transport	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
chloride channel activity	1
ion channel regulator activity	1
binding	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
cellular_component	1
cellular anatomical structure	1

Protein interactions and networks

STRING

830 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BSND	CLCNKB	P51801	997
BSND	CLCNKA	P51800	992
BSND	SLC12A1	Q13621	950
BSND	KCNJ1	P48048	913
BSND	SLC12A3	P55017	895
BSND	CLCN5	P51795	804
BSND	OSTM1	Q86WC4	670
BSND	CASR	P41180	647
BSND	REN	P00797	602
BSND	SLC9A1	P19634	595
BSND	KCNJ10	P78508	583
BSND	CLDN16	Q9Y5I7	576
BSND	MAGED2	Q9UNF1	570
BSND	CLCN1	P35523	550
BSND	SLC26A4	O43511	540

IntAct

103 interactions, top by confidence:

A	B	Type	Score
CERT1	BSND	psi-mi:“MI:0915”(physical association)	0.560
BSND	PBX3	psi-mi:“MI:0915”(physical association)	0.560
BSND	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
ARFIP1	BSND	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	BSND	psi-mi:“MI:0915”(physical association)	0.560
COL4A5	BSND	psi-mi:“MI:0915”(physical association)	0.560
PTPN9	BSND	psi-mi:“MI:0915”(physical association)	0.560
ZFPL1	BSND	psi-mi:“MI:0915”(physical association)	0.560
JAGN1	BSND	psi-mi:“MI:0915”(physical association)	0.560
PPGB	BSND	psi-mi:“MI:0915”(physical association)	0.560
ECPAS	BSND	psi-mi:“MI:0915”(physical association)	0.560
COL8A2	BSND	psi-mi:“MI:0915”(physical association)	0.560
BSND	APOL2	psi-mi:“MI:0915”(physical association)	0.560
VAMP3	BSND	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	BSND	psi-mi:“MI:0915”(physical association)	0.560
BSND	STX8	psi-mi:“MI:0915”(physical association)	0.560
BSND	SPG21	psi-mi:“MI:0915”(physical association)	0.560
GAD2	BSND	psi-mi:“MI:0915”(physical association)	0.560
ADIPOQ	BSND	psi-mi:“MI:0915”(physical association)	0.560
BSND	TBRG4	psi-mi:“MI:0915”(physical association)	0.560
BMP10	BSND	psi-mi:“MI:0915”(physical association)	0.560
BSND	TMEM60	psi-mi:“MI:0915”(physical association)	0.560
BSND	CERT1	psi-mi:“MI:0915”(physical association)	0.560
CSGALNACT2	BSND	psi-mi:“MI:0915”(physical association)	0.560
THAP4	BSND	psi-mi:“MI:0915”(physical association)	0.560
BSND	MYG1	psi-mi:“MI:0915”(physical association)	0.560
CDIPT	BSND	psi-mi:“MI:0915”(physical association)	0.560
BSND	HIP1	psi-mi:“MI:0915”(physical association)	0.560
LAMP2	BSND	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (63): FATE1 (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BSND (Two-hybrid), BMP10 (Two-hybrid)

ESM2 similar proteins: A0A1B0GU29, A2A9F4, A2ANU3, A4IFJ1, A6NDD5, A6NMD0, M3WHG5, O75298, Q08DM6, Q32M26, Q3USQ7, Q4R532, Q58DZ9, Q5BK39, Q63247, Q64322, Q68DV7, Q6AY88, Q6KAU7, Q6NUJ2, Q6ZNR0, Q76N89, Q76NI1, Q8BLR5, Q8BP99, Q8BR26, Q8BWG4, Q8BZW2, Q8C581, Q8C708, Q8IUC6, Q8IXW0, Q8K0W3, Q8NAX2, Q8NC06, Q8NDX1, Q8R2H3, Q8VIM4, Q8WV48, Q8WWG9

Diamond homologs: Q8R2H3, Q8VIM4, Q8WZ55

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	12
Uncertain significance	129
Likely benign	188
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075014	NM_057176.3(BSND):c.352C>T (p.Gln118Ter)	Pathogenic
1179115	GRCh37/hg19 1p32.3(chr1:55464606-55482845)	Pathogenic
1457051	NM_057176.3(BSND):c.290_291dup (p.Tyr98fs)	Pathogenic
1458174	NM_057176.3(BSND):c.220del (p.Ser74fs)	Pathogenic
2005597	NM_057176.3(BSND):c.163C>T (p.Gln55Ter)	Pathogenic
2030162	NM_057176.3(BSND):c.174del (p.Lys59fs)	Pathogenic
2103107	NM_057176.3(BSND):c.143dup (p.Ile49fs)	Pathogenic
2202763	NM_057176.3(BSND):c.94C>T (p.Gln32Ter)	Pathogenic
2910107	NM_057176.3(BSND):c.22C>G (p.Arg8Gly)	Pathogenic
3248022	NC_000001.10:g.(?55464860)(55505737_?)del	Pathogenic
3248023	NC_000001.10:g.(?55470675)(55474301_?)del	Pathogenic
3767333	NM_057176.3(BSND):c.556dup (p.Ala186fs)	Pathogenic
4380	NM_057176.3(BSND):c.1A>T (p.Met1Leu)	Pathogenic
4383	NM_057176.3(BSND):c.273-887_*576del	Pathogenic
4386	NM_057176.3(BSND):c.23G>T (p.Arg8Leu)	Pathogenic
4388	NM_057176.3(BSND):c.35T>C (p.Ile12Thr)	Pathogenic
4389	NM_057176.3(BSND):c.10G>T (p.Glu4Ter)	Pathogenic
4816444	NM_057176.3(BSND):c.177+2T>A	Pathogenic
858780	NM_057176.3(BSND):c.470G>A (p.Trp157Ter)	Pathogenic
1068052	NC_000001.10:g.(?55464850)(55530536_?)dup	Likely pathogenic
2039849	NM_057176.3(BSND):c.273-2A>G	Likely pathogenic
2697674	NM_057176.3(BSND):c.272+2T>C	Likely pathogenic
2812563	NM_057176.3(BSND):c.178-2A>C	Likely pathogenic
4063911	NM_057176.3(BSND):c.353_362del (p.Gln118fs)	Likely pathogenic
4063933	NM_057176.3(BSND):c.478_484dup (p.Val162fs)	Likely pathogenic
4526842	NM_057176.3(BSND):c.306G>A (p.Trp102Ter)	Likely pathogenic
4816445	NM_057176.3(BSND):c.177+2T>C	Likely pathogenic
4816446	NM_057176.3(BSND):c.325C>T (p.Gln109Ter)	Likely pathogenic
4816447	NM_057176.3(BSND):c.389_396dup (p.Ala133fs)	Likely pathogenic
4816448	NM_057176.3(BSND):c.466del (p.Ala156fs)	Likely pathogenic

SpliceAI

581 predictions. Top by Δscore:

Variant	Effect	Δscore
1:54999361:AAGG:A	donor_loss	1.0000
1:54999362:AGGT:A	donor_loss	1.0000
1:54999364:G:C	donor_loss	1.0000
1:54999365:T:G	donor_loss	1.0000
1:55005114:GAG:G	donor_gain	1.0000
1:55005117:G:C	donor_loss	1.0000
1:55005117:G:GG	donor_gain	1.0000
1:55006995:A:AG	acceptor_gain	1.0000
1:55006996:G:GA	acceptor_gain	1.0000
1:55006996:GCC:G	acceptor_gain	1.0000
1:55006996:GCCCC:G	acceptor_gain	1.0000
1:55007271:GG:G	donor_gain	1.0000
1:55007272:GG:G	donor_gain	1.0000
1:54999364:G:GG	donor_gain	0.9900
1:55005013:T:TA	acceptor_gain	0.9900
1:55005016:TTGCA:T	acceptor_loss	0.9900
1:55005017:TGCA:T	acceptor_loss	0.9900
1:55005018:GCA:G	acceptor_loss	0.9900
1:55005019:CA:C	acceptor_loss	0.9900
1:55005020:A:AG	acceptor_gain	0.9900
1:55005020:A:C	acceptor_loss	0.9900
1:55005021:G:GC	acceptor_gain	0.9900
1:55005021:G:T	acceptor_loss	0.9900
1:55005021:GATC:G	acceptor_gain	0.9900
1:55006990:A:AG	acceptor_gain	0.9900
1:55006991:C:G	acceptor_gain	0.9900
1:55006993:CCA:C	acceptor_loss	0.9900
1:55006993:CCAG:C	acceptor_gain	0.9900
1:55006994:CA:C	acceptor_loss	0.9900
1:55006994:CAGC:C	acceptor_gain	0.9900

AlphaMissense

2130 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:54999307:G:C	G41R	0.991
1:54999337:T:A	W51R	0.991
1:54999337:T:C	W51R	0.991
1:54999229:G:A	G15R	0.990
1:54999229:G:C	G15R	0.990
1:54999250:G:C	G22R	0.988
1:54999328:G:C	G48R	0.988
1:54999340:A:C	S52R	0.988
1:54999342:C:A	S52R	0.988
1:54999342:C:G	S52R	0.988
1:54999251:G:A	G22D	0.985
1:54999310:A:C	S42R	0.985
1:54999312:C:A	S42R	0.985
1:54999312:C:G	S42R	0.985
1:54999329:G:A	G48D	0.985
1:54999215:G:A	G10D	0.984
1:54999230:G:A	G15E	0.984
1:54999346:T:C	C54R	0.984
1:54999308:G:A	G41D	0.983
1:54999317:T:A	M44K	0.981
1:54999317:T:G	M44R	0.981
1:54999256:T:C	F24L	0.977
1:54999258:C:A	F24L	0.977
1:54999258:C:G	F24L	0.977
1:54999295:T:C	F37L	0.974
1:54999297:C:A	F37L	0.974
1:54999297:C:G	F37L	0.974
1:54999325:G:A	G47R	0.974
1:54999325:G:C	G47R	0.974
1:54999214:G:C	G10R	0.972

dbSNP variants (sampled 300 via entrez): RS1000230833 (1:55015481 C>A,T), RS1000260386 (1:55015679 C>G,T), RS1000265276 (1:55002404 T>G), RS1000306822 (1:55014550 T>G), RS1000422412 (1:55004019 T>C), RS1000510989 (1:54998105 C>T), RS1000697860 (1:55009078 T>C), RS1000802776 (1:55005509 C>T), RS1001066541 (1:54999555 C>A), RS1001263844 (1:55013064 A>G), RS1001305333 (1:55017096 A>G), RS1001566684 (1:54997213 C>A), RS1001703248 (1:55007802 A>G), RS1001716849 (1:55013319 A>T), RS1001975816 (1:55000642 C>G,T)

Disease associations

OMIM: gene MIM:606412 | disease phenotypes: MIM:602522, MIM:603776, MIM:601678, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
Bartter disease type 4A	Definitive	Autosomal recessive
Bartter syndrome type 4	Supportive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Bartter disease type 4A	Definitive	AR

Mondo (6): Bartter disease type 4A (MONDO:0011242), hearing loss disorder (MONDO:0005365), hypercholesterolemia, autosomal dominant, 3 (MONDO:0011369), Bartter syndrome (MONDO:0015231), Bartter syndrome type 4 (MONDO:0019524), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (4): 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)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
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:0001789	Hydrops fetalis
HP:0001919	Acute kidney injury
HP:0001944	Dehydration
HP:0001959	Polydipsia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002550_2	Allergic rhinitis	7.000000e-07
GCST007395_1	Mitochondrial DNA copy number	1.000000e-06
GCST007931_14	Medication use (HMG CoA reductase inhibitors)	5.000000e-08
GCST010151_2	Carotid intima media thickness x smoking interaction	6.000000e-06
GCST010479_75	Coronary artery disease	1.000000e-08
GCST010866_14	Coronary artery disease	2.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006312	mitochondrial DNA measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0006527	smoking status measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001477	Bartter Syndrome	C12.050.351.968.419.815.279; C12.200.777.419.815.279; C12.950.419.815.279; C19.053.800.604.249
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C564609	Deafness, Autosomal Recessive (supp.)
C566337	Hypercholesterolemia, Autosomal Dominant, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
2-methyl-4-isothiazolin-3-one	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Bucladesine	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Malathion	increases expression	1
Medroxyprogesterone Acetate	affects cotreatment, increases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss