Details for: BSND

Gene ID: 7809

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: BSND

Ensembl ID: ENSG00000162399

Description: barttin CLCNK type accessory subunit beta

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • renal alpha-intercalated cell CL0005011
    CSI 15.83
    rCSI 21.17%
    PRS 80.96
  • ionocyte CL0005006
    CSI 10.14
    rCSI 10.86%
    PRS 73.82
  • pulmonary ionocyte CL0017000
    CSI 5.9
    rCSI 7.18%
    PRS 80.17
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 2.21
    rCSI 5.71%
    PRS 68.21
  • epithelial cell CL0000066
    CSI 1.1
    rCSI 1.7%
    PRS 64.8

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary The [BSND](/details-gene/7809) gene encodes barttin, a beta-subunit protein essential for the proper function and plasma membrane localization of ClC-K type chloride channels. **Overall**, expression of [BSND](/details-gene/7809) is highly specific to specialized ion-transporting epithelial cells, most notably [renal alpha-intercalated cell](/details-cell/CL0005011) (CSI: 15.83) and [ionocyte](/details-cell/CL0005006) (CSI: 10.14). Functionally, barttin is a critical regulator of chloride transport, playing an indispensable role in renal salt reabsorption and potassium secretion in the inner ear. Mutations in [BSND](/details-gene/7809) are the cause of Bartter syndrome type IV ([602522](https://omim.org/entry/602522)), a severe inherited disorder characterized by kidney failure and congenital sensorineural deafness, as established in foundational research ([Link](https://doi.org/10.1038/ng752), [Link](https://doi.org/10.1038/35107099)). ## Cellular Roles and Expression Landscape The expression profile of [BSND](/details-gene/7809) highlights its specialized role in maintaining ion homeostasis across specific epithelial barriers. The gene's significance is exceptionally high in cells dedicated to ion exchange, suggesting it is a defining functional marker for these cell types. **Overall**, the highest significance scores are observed in: * **[Renal alpha-intercalated cell](/details-cell/CL0005011)** (CSI: 15.83), which are critical for acid-base homeostasis in the kidney's collecting ducts. * **[Ionocyte](/details-cell/CL0005006)** (CSI: 10.14) and **[pulmonary ionocyte](/details-cell/CL0017000)** (CSI: 5.90), cell types known for their high density of ion channels and transporters in various tissues, including gills and airways. * **[Kidney loop of Henle thin ascending limb epithelial cell](/details-cell/CL1001107)** (CSI: 2.21), which participates in the countercurrent mechanism for urine concentration. This restricted and high-level expression pattern is consistent with barttin's role as an essential accessory subunit, without which ClC-K channels are non-functional ([Link](https://doi.org/10.1073/pnas.0601631103)). Its activity within these specific cells is crucial for systemic electrolyte balance and the generation of the endocochlear potential required for hearing. ## Pathways and Molecular Function The molecular functions and pathway involvements of [BSND](/details-gene/7809) are tightly linked to its cellular expression pattern. According to Gene Ontology annotations, barttin is directly involved in [Chloride transmembrane transport](/details-cell/GO1902476) and functions as a [Chloride channel regulator activity](/details-cell/GO0017081). It is an integral component of the [basolateral plasma membrane](/details-cell/GO0016323), where it co-localizes with and stabilizes ClC-K channels. This regulatory function is a key part of broader physiological processes, including the Reactome pathways for [Ion channel transport](/details-pathway/R-HSA-983712) and the [Transport of small molecules](/details-pathway/R-HSA-382551). The clinical phenotype associated with [BSND](/details-gene/7809) mutations is explained by the disruption of these pathways; impaired chloride transport in the kidney leads to salt-wasting and electrolyte imbalance, while its disruption in the inner ear underlies the [sensory perception of sound](/details-cell/GO0007605) defect, causing deafness ([Link](https://doi.org/10.1038/35107099)). Studies have confirmed that barttin not only facilitates the trafficking of ClC-K channels to the cell surface but also modulates their gating properties, directly impacting channel activity ([Link](https://doi.org/10.1681/asn.2009121274), [Link](https://doi.org/10.1007/s00424-002-0819-8)). ## Research Directions The well-defined monogenic disease linkage of [BSND](/details-gene/7809) provides a clear foundation for translational research, yet specific aspects of its function and the phenotypic variability of its mutations warrant further investigation. ### Proposed Hypotheses: 1. **Differential Channel Affinity Hypothesis:** Given that some [BSND](/details-gene/7809) mutations cause non-syndromic deafness (DFNB73) while others cause the full spectrum of Bartter syndrome type IV ([Link](https://doi.org/10.1016/j.ajhg.2009.07.003)), it is hypothesized that specific pathogenic variants differentially disrupt barttin's interaction with the two different ClC-K isoforms (ClC-Ka in the kidney and inner ear; ClC-Kb primarily in the kidney). Mutations causing only deafness may selectively impair the function of the ClC-Ka/barttin complex while largely preserving ClC-Kb/barttin function. 2. **Modifier Gene Hypothesis in Respiratory Disease:** The significant expression of [BSND](/details-gene/7809) in [pulmonary ionocyte](/details-cell/CL0017000), a cell type implicated in airway surface liquid homeostasis, suggests that non-pathogenic variants in [BSND](/details-gene/7809) may act as genetic modifiers for diseases like cystic fibrosis. These variants could subtly alter chloride transport in the airways, exacerbating or mitigating disease severity in individuals with primary defects in other ion channels, such as CFTR. ### Key Experiment: To test the **Differential Channel Affinity Hypothesis**, a series of electrophysiological experiments could be conducted. * **Approach:** Use a heterologous expression system, such as *Xenopus laevis* oocytes or HEK293T cells, to co-express human ClC-Ka or ClC-Kb with either wild-type or mutant [BSND](/details-gene/7809) constructs (e.g., a deafness-only variant vs. a Bartter syndrome variant). * **Methodology:** Chloride currents would be measured using two-electrode voltage-clamp or whole-cell patch-clamp techniques. In parallel, surface expression levels of the channel/subunit complexes could be quantified using cell-surface biotinylation assays followed by Western blotting. * **Expected Outcome:** This would directly determine whether specific mutations lead to a selective loss of function (e.g., reduced current or impaired trafficking) for one ClC-K isoform over the other, providing a mechanistic explanation for the observed clinical heterogeneity. ### Therapeutic Potential As Bartter syndrome type IV is a loss-of-function disorder, the therapeutic goal is to restore barttin's function. Inhibition of [BSND](/details-gene/7809) is not a viable strategy. * **Gene Therapy:** AAV-mediated gene replacement, delivering a functional copy of [BSND](/details-gene/7809) to affected cells in the kidney's thick ascending limb and the inner ear's stria vascularis, represents a potential curative approach. However, targeted and safe delivery to these specific tissues remains a major challenge. * **Pharmacological Chaperones:** For missense mutations that cause protein misfolding and retention in the endoplasmic reticulum ([Link](https://doi.org/10.1681/asn.2008010102)), the development of small molecule chaperones could be a promising strategy. Such molecules would aim to correct the folding of the mutant barttin protein, enabling its proper trafficking to the plasma membrane to restore at least partial ClC-K channel function.

Genular Protein ID: 3860190834

Symbol: BSND_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q8WZ55 Q6NT28

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 2 Ensembl 1 ExpressionAtlas 1 GO 7 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 STRING 1 SignaLink 1 SwissPalm 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 11687798

Title: Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.

PubMed ID: 11687798

DOI: 10.1038/ng752

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 11734858

Title: Barttin is a Cl- channel beta-subunit crucial for renal Cl-reabsorption and inner ear K+ secretion.

PubMed ID: 11734858

DOI: 10.1038/35107099

PubMed ID: 12111250

Title: Barttin increases surface expression and changes current properties of ClC-K channels.

PubMed ID: 12111250

DOI: 10.1007/s00424-002-0819-8

PubMed ID: 12761627

Title: Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene.

PubMed ID: 12761627

DOI: 10.1007/s00418-003-0535-2

PubMed ID: 16849430

Title: Barttin modulates trafficking and function of ClC-K channels.

PubMed ID: 16849430

DOI: 10.1073/pnas.0601631103

PubMed ID: 18776122

Title: Disease-causing dysfunctions of barttin in Bartter syndrome type IV.

PubMed ID: 18776122

DOI: 10.1681/asn.2008010102

PubMed ID: 20538786

Title: Barttin activates ClC-K channel function by modulating gating.

PubMed ID: 20538786

DOI: 10.1681/asn.2009121274

PubMed ID: 26013830

Title: Human CLC-K channels require palmitoylation of their accessory subunit barttin to be functional.

PubMed ID: 26013830

DOI: 10.1074/jbc.m114.631705

PubMed ID: 12574213

Title: Atypical Bartter syndrome with sensorineural deafness with G47R mutation of the beta-subunit for ClC-Ka and ClC-Kb chloride channels, barttin.

PubMed ID: 12574213

DOI: 10.1210/jc.2002-021398

PubMed ID: 16328537

Title: A compound heterozygous mutation in the BSND gene detected in Bartter syndrome type IV.

PubMed ID: 16328537

DOI: 10.1007/s00467-005-2091-6

PubMed ID: 16773427

Title: Barttin mutations in antenatal Bartter syndrome with sensorineural deafness.

PubMed ID: 16773427

DOI: 10.1007/s00467-006-0108-4

PubMed ID: 19646679

Title: Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome.

PubMed ID: 19646679

DOI: 10.1016/j.ajhg.2009.07.003

Sequence Information:

  • Length: 320
  • Mass: 35197
  • Checksum: DED232CAF85AE5AA
  • Sequence:
    • MADEKTFRIG FIVLGLFLLA LGTFLMSHDR PQVYGTFYAM GSVMVIGGII WSMCQCYPKI 
TFVPADSDFQ GILSPKAMGL LENGLAAEMK SPSPQPPYVR LWEEAAYDQS LPDFSHIQMK 
VMSYSEDHRS LLAPEMGQPK LGTSDGGEGG PGDVQAWMEA AVVIHKGSDE SEGERRLTQS 
WPGPLACPQG PAPLASFQDD LDMDSSEGSS PNASPHDREE ACSPQQEPQG CRCPLDRFQD 
FALIDAPTLE DEPQEGQQWE IALPNNWQRY PRTKVEEKEA SDTGGEEPEK EEEDLYYGLP 
DGAGDLLPDK ELGFEPDTQG