Disease relevance of BSND

• A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p [1].
• A new distinct group in Bartter syndrome accompanied by sensorineural deafness (BSND) has been identified among the IBS patients [2].
• However, the clinical feature in the patient lacking the characteristic symptoms of IBS such as polyhydramnios, premature labor, or severe salt loss in neonatal period contrasts with that of the typical BSND patients described so far in the literature [2].
• At least two (Cockayne-Touraine and Bart) of the three subtypes of dominant dystrophic epidermolysis bullosa seem to represent different forms of expression of the same gene defect [3].
• Candidate sequences were suggested by mapping a region of unmethylated DNA in EBV around the BART promoter followed by in vivo footprinting the promoter in the C666-1 nasopharyngeal carcinoma cell line, which expresses BART RNAs [4].

High impact information on BSND

• Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure [1].
• In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear [1].
• We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND [1].
• In this study, we examined the effects of barttin on two ClC-K channel isoforms, rat ClC-K1 and human ClC-Kb, using heterologous expression, patch clamping, confocal imaging, and flow cytometry [5].
• In the absence of barttin, only a small percentage of rClC-K1 and hClC-Kb channels are inserted into the plasma membrane [5].

Chemical compound and disease context of BSND

• Atypical Bartter syndrome with sensorineural deafness with G47R mutation of the beta-subunit for ClC-Ka and ClC-Kb chloride channels, barttin [2].

Biological context of BSND

• The down-regulation of ClC-Ka/barttin by Nedd4-2 was abolished by elimination of the PY motif in barttin [6].
• Nearly 60% of all individuals reaching mating age on "St. Bart" never contribute to the gene pool of succeeding generations [7].
• The 489-base pair BART open reading frame encodes a novel 163-amino acid protein with a predicted molecular mass of 18,822 Da [8].
• This alteration results in a missense mutation, G47R, which has been previously shown to abolish the stimulatory effect on the subunit barttin of the ClC-Kb channel [9].
• The latter also had -alpha mutation on the other chromosome, giving rise to the genotype alpha cs alpha/-alpha, which produced high Hb Bart. The gene frequency for alpha cs in the Thai calculated from a total of 406 cord blood studied in Bangkok was found to be approximately 0.008 [10].

Anatomical context of BSND

• Barttin is an accessory subunit of a subgroup of ClC-type chloride channels expressed in renal and inner ear epithelia [5].
• METHODS: After heterologous expression in Xenopus oocytes, ClC-Kb channel activity and surface expression in presence of the ClC-K beta subunit barttin were determined by two-electrode voltage-clamp analysis, immunofluorescence, and ClC-Kb surface enzyme-linked immunosorbent assay (ELISA) [11].
• In addition, we generated several stable cell lines expressing mutant barttins to clarify the consequence of the previously reported barttin mutations in Bartter syndrome [12].
• This led to a retention of CLC-K2 in intracellular organelles with barttin, and a loss of plasma membrane localization [12].
• Both ARL2 and BART are predominantly cytosolic, but a pool of each was found associated with mitochondria in a protease-resistant form [13].

Associations of BSND with chemical compounds

• ARL2 and BART enter mitochondria and bind the adenine nucleotide transporter [13].
• In addition, we summarize the results obtained with other inhibitors of the enzyme; for instance, polyhydroxy-substituted benzohydroxamic acid derivatives, a promising group of inhibitors of ribonucleotide reductase that was synthesized by Bart van'T Riet and investigated by our group [14].
• Brine shrimp lethality-directed fractionation of the 95% EtOH extract of the powdered, dried berries of Serenoa repens (Bart.) Small (saw-palmetto) (Palmae) led to the isolation of two monoacylglycerides, 1-monolaurin (1) and 1-monomyristin (2) [15].
• Selective enzymatic amplification of the alpha 2-globin gene and allele-specific hybridization for Hb CS gene provided accurate diagnosis of Hb Constant Spring. We have used this approach to detect the alpha cs mutation in the cord blood that contained all four alpha-globin genes but had Hb Bart on electrophoresis [10].
• Tonofilament deficiency, found in one family with congenital skin defects, was classified as EB Bart, and in one family a deficiency in one enzyme of collagen synthesis, galactosylhydroxylysine glucosyltransferase activity in skin and serum, was found to correlate significantly with severity of EB simplex Köbner (VI) [16].

Regulatory relationships of BSND

• CONCLUSION: ClC-Ka/barttin channels are regulated by SGK1 and SGK3, which may thus participate in the regulation of transport in kidney and inner ear [6].
• RESULTS: Expression of ClC-Ka/barttin induced a slightly inwardly rectifying current that was significantly decreased upon coexpression of Nedd4-2, but not the catalytically inactive mutant C938SNedd4-2 [6].

Other interactions of BSND

• Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases [6].
• New information about the physiological regulation of renal ClC proteins has implicated the Nedd4 ubiquitin ligases and serum and glucocorticoid-inducible kinases in controlling functional levels of ClC-5 and ClC-K/barttin in renal cells [17].

Analytical, diagnostic and therapeutic context of BSND

• Western blotting confirmed that Calu-3 cells express both ClC-K and barttin protein [18].
• Sequence analysis of the BSND gene showed that the affected members were homozygous for a C-to-T transition in exon 1, while their parents were heterozygous [9].
• In immunocytochemistry, CLC-K2 was retained in the Golgi in the absence of barttin expression, but delivered to the plasma membrane when barttin was present [12].
• We found that BART miRNAs but not BHRF1 miRNAs were expressed in EBV-infected gastric carcinoma cell lines and the tumor tissues from patients as well as the animal model [19].
• Important differential diagnoses are the syndrome of scalp defect and postaxial polydactyly, the syndrome of scalp defect and split-hand defect, amniotic band sequence, and epidermolysis bullosa dystrophica type Bart [20].

References