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BSND
barttin CLCNK type accessory subunit beta
The BSND gene encodes the barttin protein, crucial for the proper function of chloride channels in the kidneys and inner ear, which are involved in fluid balance and hearing. The BSND gene provides instructions for producing barttin, a protein essential for the stability and function of specific chloride channels.
BSND is located on the short (p) arm of chromosome 1, at band 1p32.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The BSND gene, also known as barttin CLCNK type accessory subunit beta, provides the genetic blueprint for a protein called barttin. This protein is critical for regulating the activity of chloride channels, specifically ClC-Ka and ClC-Kb, which are found predominantly in the kidneys and the inner ear. Proper functioning of these channels, facilitated by barttin, is vital for maintaining the body's fluid and electrolyte balance and for normal auditory processes.
Dysfunction of the BSND gene can lead to inherited conditions, most notably a severe form of Bartter syndrome, which often includes associated hearing loss. Understanding the role of BSND is key to comprehending these complex physiological processes and related health issues.
What the gene does
The barttin protein, encoded by the BSND gene, serves as an essential accessory subunit for the ClC-Ka and ClC-Kb chloride channels. In the kidneys, barttin binds to these channels, facilitating their correct positioning within the cell membrane and ensuring their stable and effective operation. These chloride channels are integral to the process by which kidneys reabsorb salt, specifically chloride ions, from filtered urine back into the bloodstream.
This salt reabsorption mechanism is fundamental for regulating the body's fluid levels and plays a significant role in maintaining blood pressure. Beyond the kidneys, barttin, along with ClC-Ka and ClC-Kb, is also present in the inner ear, where their coordinated activity is necessary for normal hearing. Therefore, the barttin protein is indispensable for both renal physiological functions and auditory system integrity.
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Chromosome location
The BSND gene is situated on chromosome 1, specifically at position 1p32.3. This genomic location describes the precise address of the gene within the human genome. The gene's presence at this band on the short arm of chromosome 1 underscores its fixed position and potential influence on nearby genetic regions.
Protein structure
The barttin protein consists of 320 amino acids. Its structure includes a region spanning amino acids 1-72 that is responsible for regulating channel membrane trafficking and ion conductance. Additionally, the protein contains two disordered regions, one located between amino acids 167 and 233, and another from amino acids 250 to 320. These disordered segments may contribute to the protein's flexibility and interactions with other cellular components.
Key variants
Variants within the BSND gene can alter the structure or function of the barttin protein, leading to its impaired ability to regulate chloride channels. These genetic changes can range from small alterations in the DNA sequence to larger deletions or insertions. Such pathogenic variants typically result in a non-functional or improperly functioning barttin protein, which then affects critical physiological processes in the kidneys and inner ear.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.10G>T | p.Glu4Ter | Pathogenic | ★★☆☆ | Bartter syndrome |
c.143del | p.Gly48fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
c.262G>T | p.Glu88Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter disease type 4A |
c.272+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
c.283C>T | p.Gln95Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
c.305G>A | p.Trp102Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
c.318del | p.Tyr107fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
c.35T>C | p.Ile12Thr | Pathogenic | ★★☆☆ | Bartter syndrome |
c.442G>T | p.Glu148Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
c.97G>C | p.Val33Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the BSND gene are primarily associated with inherited conditions such as Bartter syndrome. Specifically, these variants can cause Bartter syndrome (AR), often referred to as Bartter syndrome type IV. This form of Bartter syndrome is frequently severe, with symptoms appearing either before or shortly after birth. Individuals affected by Bartter syndrome type IV also commonly experience hearing loss due to abnormalities in the inner ear.
Inheritance pattern
Conditions caused by pathogenic BSND variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The BSND gene is recognised within the NHS Genomic Medicine Service due to its clinical significance. It is listed on several NHS Genomic Test Directories via PanelApp, including those for DDG2P, Foetal anomalies (R21), Monogenic hearing loss (R67), Nephrocalcinosis or nephrolithiasis (R256), and Renal tubulopathies (R198), all of which are categorised as 'green'. This indicates that there is strong evidence for a gene-disease association and that testing for BSND variants is routinely considered for individuals presenting with related clinical features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the BSND gene?
The BSND gene provides instructions for making the barttin protein, which is essential for the proper function and stability of specific chloride channels (ClC-Ka and ClC-Kb) in the kidneys and inner ear.
What health conditions are associated with variants in the BSND gene?
Variants in the BSND gene are primarily associated with Bartter syndrome (AR), particularly Bartter syndrome type IV, which can present with severe symptoms and often includes hearing loss.
How is Bartter syndrome type IV inherited?
Bartter syndrome type IV caused by BSND gene variants is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.
References
- Janssen AG, Scholl U, Domeyer C. Disease-causing dysfunctions of barttin in Bartter syndrome type IV. Journal of the American Society of Nephrology : JASN. 2009. PMID: 18776122
- Riazuddin S, Anwar S, Fischer M. Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. American journal of human genetics. 2009. PMID: 19646679
- Krämer BK, Bergler T, Stoelcker B. Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance. Nature clinical practice. Nephrology. 2008. PMID: 18094726
- Scholl U, Hebeisen S, Janssen AG. Barttin modulates trafficking and function of ClC-K channels. Proceedings of the National Academy of Sciences of the United States of America. 2006. PMID: 16849430
- Miyamura N, Matsumoto K, Taguchi T. Atypical Bartter syndrome with sensorineural deafness with G47R mutation of the beta-subunit for ClC-Ka and ClC-Kb chloride channels, barttin. The Journal of clinical endocrinology and metabolism. 2003. PMID: 12574213
- Hayama A, Rai T, Sasaki S. Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. Histochemistry and cell biology. 2003. PMID: 12761627
- Birkenhäger R, Otto E, Schürmann MJ. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nature genetics. 2001. PMID: 11687798
- Estévez R, Boettger T, Stein V. Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. Nature. 2001. PMID: 11734858