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

Abstract

Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. 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. 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. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. 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. The gene encodes a hitherto unknown protein with two putative transmembrane alpha-helices and thus might function as a regulator for ion-transport proteins involved in aBS, or else as a new transporter or channel itself.

Functional Characterization of a Calcium-Sensing Receptor Mutation in Severe Autosomal Dominant Hypocalcemia with a Bartter-Like Syndrome

“…Finally, mutations in the CLCNKB gene, which codes for the basolateral renal chloride channel CLC-kb, are responsible for most of the cases of the classical variant, which is characterized by a milder phenotype beginning in infancy or childhood, hypomagnesemia in 40% of cases, and normo-or hypercalciuria (25,26). Recently, a new gene (BSND) responsible for the antenatal variant of Bartter syndrome with sensorineural deafness has been identified (27). This new gene encodes a new protein, barttin, which acts as an essential ␤-subunit for basolateral ClC-ka and ClC-kb channels (28).…”

Rare independent mutations in renal salt handling genes contribute to blood pressure variation

“…Bartter's syndrome features massive renal salt wasting and hypotension, often resulting in neonatal death. It is caused by recessive loss of function mutations in any of 4 genes required for normal renal NaCl reabsorption [12][13][14][15] . These include the Na-K-2Cl cotransporter SLC12A1 and the inward rectifier K + channel KCNJ1.…”

Genetics of arterial hypertension and hypotension

“…Inactivating mutations in Barttin give rise to a fourth type of Bartter's syndrome, again with familial hypotension, but complicated by sensorineural deafness attributable to the role of chloride channels in epithelia of the inner ear ( Fig. 12; Birkenhager et al 2001). …”