BSND – Bartter syndrome type 4

Bartter syndrome type 4 (BS type IV) is an autosomal recessive renal salt-wasting tubulopathy characterized by hypokalemic metabolic alkalosis, polyuria, sensorineural hearing impairment, and polyhydramnios, resulting from loss-of-function mutations in BSND, which encodes barttin, the accessory subunit of ClC-K chloride channels (PMID:12761627).

Genetic evidence includes at least 14 probands across more than six unrelated families presenting homozygous or compound heterozygous BSND variants. A recurrent missense allele c.139G>A (p.Gly47Arg) has been reported in Korean and European patients (n=3 sibs and 2 additional unrelated probands) with consistent perinatal BS IV features (PMID:21158220, PMID:21269598, PMID:31667618). A novel frameshift insertion, c.305_306insT (p.Trp102ValfsTer7), was identified in a female neonate with early-onset renal failure and deafness (PMID:23110775).

The variant spectrum encompasses missense substitutions (e.g., p.Arg8Trp, p.Arg8Gly, p.Thr36Asn, p.Gly47Arg), nonsense alleles (e.g., p.Gln32Ter), and frameshift mutations (p.Trp102ValfsTer7). Two novel homozygous missense mutations, p.Arg8Gly and p.Thr36Asn, were discovered in seven Moroccan patients from two unrelated pedigrees (PMID:30174009). Digenic interactions with GJB2 alleles have been reported but are not required for BS IV phenotype (PMID:28012523).

Segregation analysis confirms autosomal recessive inheritance, with three affected brothers homozygous for p.Gly47Arg showing concordant clinical features and obligate carrier parents (PMID:21269598). Additional familial segregation data from Moroccan kindreds support variant pathogenicity.

Functional studies demonstrate that disease-causing barttin mutants (R8L, R8W, G10S) impair ClC-K plasma membrane localization by ER retention, reducing chloride current, whereas G47R shows partial binding but decreased channel activation (PMID:18776122). Co-expression assays in mammalian cells revealed that barttin is necessary for ClC-K2 trafficking to the cell surface (PMID:12761627). In vivo, Hsp90 inhibition with 17-AAG rescues ER-retained mutants (R8L, G47R) in Bsnd(R8L/R8L) knock-in mice, normalizing electrolyte balance and hearing (PMID:24189473).

Conflicting data include the BSND p.Val43Ile variant, common in normotensive populations and exhibiting partial loss of function without clinical hypertension association (PMID:17954364). No refuting evidence for BS type IV association has been reported.

Collectively, genetic and experimental data establish a strong autosomal recessive gene-disease relationship for BSND in Bartter syndrome type IV. These insights support molecular diagnosis, genetic counseling, and potential chaperone-based therapies. Key take-home: BSND loss-of-function variants cause sensorineural deafness and renal salt wasting via barttin mislocalization, amenable to functional rescue.

References

• Histochemistry and cell biology • 2003 • Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. PMID:12761627
• Journal of pediatric endocrinology & metabolism • 2010 • A case of antenatal Bartter syndrome with sensorineural deafness. PMID:21158220
• Clinical nephrology • 2011 • Renal dysfunction and barttin expression in Bartter syndrome Type IV associated with a G47R mutation in BSND in a family. PMID:21269598
• Clinical nephrology • 2014 • Severe manifestation of Bartter syndrome Type IV caused by a novel insertion mutation in the BSND gene. PMID:23110775
• International journal of pediatric otorhinolaryngology • 2018 • Two novel homozygous missense mutations identified in the BSND gene in Moroccan patients with Bartter's syndrome. PMID:30174009
• Journal of the American Society of Nephrology : JASN • 2009 • Disease-causing dysfunctions of barttin in Bartter syndrome type IV. PMID:18776122
• 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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