BSND – Bartter Disease Type 4A

BSND encodes barttin, an essential β-subunit for the ClC-Ka and ClC-Kb chloride channels expressed in the basolateral membrane of the renal thick ascending limb and the stria vascularis of the inner ear. Bi-allelic loss-of-function variants in BSND lead to Bartter disease type 4A, characterized by antenatal polyhydramnios, premature birth, hypokalemic salt wasting, and sensorineural deafness. The inheritance is autosomal recessive. Diagnosis relies on identification of pathogenic BSND variants in conjunction with clinical features. Genetic testing for BSND should be considered in patients presenting with antenatal salt-wasting and early-onset deafness. This summary integrates genetic and functional data to support diagnostic decision-making and potential therapeutic strategies.

In two unrelated Spanish families from the Canary Islands, five affected individuals were homozygous for the c.139G>C (p.Gly47Arg) variant in BSND, while unaffected parents were heterozygous, consistent with segregation in an autosomal recessive pattern (PMID:16572343). These five probands exhibited polyhydramnios and premature birth but maintained normal glomerular filtration rates. No other BSND variants were reported in these families. The c.139G>C (p.Gly47Arg) alteration abolishes the stimulatory effect of barttin on ClC-Kb channel activity. This variant has been classified as pathogenic in ClinVar and observed in multiple cohorts with Bartter disease type 4A. The robust co-segregation across two families supports a strong genetic link.

Functional assays demonstrate that wild-type barttin co-expression with CLC-K2 channels promotes plasma membrane localization and enhances chloride currents, whereas disease-causing barttin mutants, including R8L, are retained intracellularly, sequestering CLC-K2 in the Golgi (PMID:12761627). Specifically, the G47R variant, though capable of associating with CLC-K channels, shows reduced binding affinity, resulting in diminished channel activation and membrane insertion. Protein–protein interaction studies confirm a direct complex between barttin and CLC-K channels, critical for channel trafficking. These in vitro findings elucidate haploinsufficiency as the pathogenic mechanism. Concordance between cellular mislocalization and clinical phenotype underscores the functional relevance. Such mechanistic clarity supports targeted molecular diagnostics and phenotypic correlation.

In Bsnd^R8L/R8L knock-in mice, mutant barttin is similarly retained in the endoplasmic reticulum, leading to hypokalemia, metabolic alkalosis, and hearing impairment mirroring human Bartter disease type 4A. Treatment with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) enhances plasma membrane expression of G47R and R8L barttin variants, rescuing renal and auditory phenotypes in vivo (PMID:24189473). This pharmacological correction of protein trafficking demonstrates proof-of-concept for small-molecule therapy. The rescue effect was observed in both kidney and inner ear, highlighting systemic benefit. These data identify molecular chaperone modulation as a viable therapeutic approach. The translational potential of 17-AAG and related compounds warrants further clinical investigation.

A common BSND variant V43I exhibits partial loss-of-function in vitro but shows no association with hypertension in population studies, indicating variant-specific effects and phenotypic heterogeneity (PMID:17954364). The absence of a clear protective or deleterious effect in large cohorts suggests BSND-V43I is not clinically relevant for Bartter disease type 4A. This distinction from pathogenic alleles underscores the importance of functional validation in variant interpretation. No studies have directly refuted the association between G47R and Bartter disease type 4A. Thus, current evidence remains consistent with an autosomal recessive loss-of-function model. Ongoing surveillance for additional BSND alleles will refine genotype–phenotype correlations.

In summary, strong genetic and experimental data establish BSND as the causative gene for Bartter disease type 4A. The c.139G>C (p.Gly47Arg) variant segregates in multiple families and disrupts barttin-mediated chloride channel trafficking. Functional rescue in cell and animal models highlights a targetable mechanism of disease. Genetic testing for BSND variants should be included in diagnostic panels for antenatal salt-wasting and early deafness. Emerging small-molecule therapies such as Hsp90 modulation offer a promising avenue for treatment. Key take-home: BSND variant screening enables accurate diagnosis and provides a mechanistic framework for personalized therapeutic strategies.

References

• Pediatric nephrology (Berlin, Germany) • 2006 • Mutation G47R in the BSND gene causes Bartter syndrome with deafness in two Spanish families. PMID:16572343
• Histochemistry and cell biology • 2003 • Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. PMID:12761627
• Biochemical and biophysical research communications • 2013 • Treatment with 17-allylamino-17-demethoxygeldanamycin ameliorated symptoms of Bartter syndrome type IV caused by mutated Bsnd in mice. PMID:24189473
• American journal of hypertension • 2007 • Functional BSND variants in essential hypertension. PMID:17954364

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