BSND Mutations Research Articles

Hypokalemia and hearing loss in a 3-year-old boy: Questions.

Bartter syndrome with sensorineural deafness (Bartter syndrome type 4) is an autosomal recessive disorder characterized with polyhydramniosis, premature birth, massive polyuria, renal salt-wasting, hypokalemic metabolic alkalosis, normotensive hyperreninemic hyperaldosteronism, and hearing loss. Homozygous mutations in BSND, CLCNKA, and CLCNKB mutations cause the disorder. Here we report a 3-year-old boy who had not been evaluated and investigated before cochlear implantation. Hypokalemia was detected during the routine laboratory workup before surgery. Further analyses revealed metabolic alkalosis with high renin and aldosterone levels. Hypokalemia improved with oral potassium chloride supplementation. Genetic tests revealed a homozygous c.139G>A (pG47R) mutation in BSND gene, and both parents were heterozygous for the same mutation. We want to emphasize the importance of evaluating hearing loss in children, since some of the genetic syndromes may cause life threatening abnormalities.

Clinical and diagnostic features of Bartter and Gitelman syndromes.

ABSTRACTBackgroundBartter and Gitelman syndromes are autosomal recessive disorders of renal tubular salt handling. Due to their rarity, limited long-term data are available to inform prognosis and management.MethodsLong-term longitudinal data were analysed for 45 children with pathogenic variants in SLC12A1 (n = 8), KCNJ1 (n = 8), CLCNKB (n = 17), BSND (n = 2) and SLC12A3 (n = 10) seen at a single centre between 1984 and 2014. Median follow-up was 8.9 [interquartile range (IQR) 0.7–18.1] years.ResultsPolyhydramnios and prematurity were seen in children with SLC12A1 and KCNJ1 mutations. Patients with CLCNKB mutations had the lowest serum potassium and serum magnesium and the highest serum bicarbonate levels. Fractional excretion of chloride was >0.5% in all patients prior to supplementation. Nephrocalcinosis at presentation was present in the majority of patients with SLC12A1 and KCNJ1 mutations, while it was only present in one patient with CLCNKB and not in SLC12A3 or BSND mutations. Growth was impaired, but within the normal range (median height standard deviation score −1.2 at the last follow-up). Impaired estimated glomerular filtration rate (eGFR <90 mL/min/1.73 m2) at the last follow-up was seen predominantly with SLC12A1 [71 mL/min/1.73 m2 (IQR 46–74)] and KCNJ1 [62 mL/min/1.73 m2 (IQR 48–72)] mutations. Pathological albuminuria was detected in 31/45 children.ConclusionsPatients with Bartter and Gitelman syndromes had a satisfactory prognosis during childhood. However, decreased eGFR and pathologic proteinuria was evident in a large number of these patients, highlighting the need to monitor glomerular as well as tubular function. Electrolyte abnormalities were most severe in CLCNKB mutations both at presentation and during follow-up. Fractional excretion of chloride prior to supplementation is a useful screening investigation in children with hypokalaemic alkalosis to establish renal salt wasting.

Severe manifestation of Bartter syndrome Type IV caused by a novel insertion mutation in the BSND gene

Bartter syndrome Type IV is a rare subtype of the Bartter syndromes that leads to both severe renal salt wasting and sensorineural deafness. This autosomal recessive disease is caused by mutations in the gene encoding barttin, BSND, an essential subunit of the ClC-K chloride channels expressed in renal and inner ear epithelia. Patients differ in the severity of renal symptoms, which appears to depend on the modification of channel function by the mutant barttin. To date, only a few BSND mutations have been reported, most of which are missense or nonsense mutations. In this study, we report the identification of the first insertion mutation, p.W102Vfs*7, in the BSND gene of a newborn girl with acute clinical symptoms including early-onset chronic renal failure. The results support previous data indicating that mutations that are predicted to abolish barttin expression are associated with a severe phenotype and early onset renal failure.

Aquaporin-2: new mutations responsible for autosomal-recessive nephrogenic diabetes insipidus-update and epidemiology.

It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a ‘pure’ type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride and calcium. Patients with hereditary hypokalemic salt-losing tubulopathies have a complex phenotype with loss of water and ions. They have polyhydramnios, hypercalciuria and hypo- or isosthenuria and were found to bear KCNJ1 (ROMK) and SLC12A1 (NKCC2) mutations. Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations. These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu. This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

Identification of Missense Mutation (I12T) in the BSND Gene and Bioinformatics Analysis

Nonsyndromic hearing loss is a paradigm of genetic heterogeneity with 85 loci and 39 nuclear disease genes reported so far. Mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness and nonsyndromic nearing loss. We studied a Pakistani consanguineous family. Clinical examinations of affected individuals did not reveal the presence of any associated signs, which are hallmarks of the Bartter syndrome type IV. Linkage analysis identified an area of 18.36 Mb shared by all affected individuals between markers D1S2706 and D1S1596. A maximum two-point LOD score of 2.55 with markers D1S2700 and multipoint LOD score of 3.42 with marker D1S1661 were obtained. BSND mutation, that is, p.I12T, cosegregated in all extant members of our pedigree. BSND mutations can cause nonsyndromic hearing loss, and it is a second report for this mutation. The respected protein, that is, BSND, was first modeled, and then, the identified mutation was further analyzed by using different bioinformatics tools; finally, this protein and its mutant was docked with CLCNKB and REN, interactions of BSND, respectively.

Molecular Basis of DFNB73: Mutations of BSND Can Cause Nonsyndromic Deafness or Bartter Syndrome

BSND encodes barttin, an accessory subunit of renal and inner ear chloride channels. To date, all mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness. We identified a BSND mutation (p.I12T) in four kindreds segregating nonsyndromic deafness linked to a 4.04-cM interval on chromosome 1p32.3. The functional consequences of p.I12T differ from BSND mutations that cause renal failure and deafness in Bartter syndrome type IV. p.I12T leaves chloride channel function unaffected and only interferes with chaperone function of barttin in intracellular trafficking. This study provides functional data implicating a hypomorphic allele of BSND as a cause of apparent nonsyndromic deafness. We demonstrate that BSND mutations with different functional consequences are the basis for either syndromic or nonsyndromic deafness.

Deletion of exons 2–4 in the BSND gene causes severe antenatal Bartter syndrome

BSND gene mutations usually cause severe forms of antenatal Bartter syndrome and sensorineural deafness (SND). Chronic renal failure and transient hypercalciuria are reported as controversial symptoms of this syndrome. All twelve reported BSND mutations cause SND, whereas only two of the mutations give rise to normal glomerular filtration rate (GFR) and two other mutations cause hypercalciuria. The case we report here, where the patient presented with severe clinical symptoms and deletion on exons 2-4 of the BSND gene, has not been reported previously. Decreased GFR, along with hypercalciuria and difficulties in managing fluid and electrolyte requirements, are the reasons why this patient was brought to attention.

Phenotype–genotype correlation in antenatal and neonatal variants of Bartter syndrome

Ante/neonatal Bartter syndrome (BS) is a hereditary salt-losing tubulopathy due to mutations in genes encoding proteins involved in NaCl reabsorption in the thick ascending limb of Henle's loop. Our aim was to study the frequency, clinical characteristics and outcome of each genetic subtype. Charts of 42 children with mutations in KCNJ1 (n = 19), SLC12A1 (n = 13) CLCNKB (n = 6) or BSND (n = 4) were retrospectively analysed. The median follow-up was 8.3 [0.4-18.0] years. We describe 24 new mutations: 10 in KCNJ1, 11 in SLC12A1 and 3 in CLCNKB. The onset of polyhydramnios, birth term, height and weight were similar for all groups; three patients had no history of polyhydramnios or premature birth and had CLCNKB mutations according to a less severe renal sodium wasting. Contrasting with these data, patients with CLCNKB had the lowest potassium (P = 0.006 versus KCNJ1 and P = 0.034 versus SLC12A1) and chloride plasma concentrations (P = 0.039 versus KCNJ1 and P = 0.024 versus SLC12A1) and the highest bicarbonataemia (P = 0.026 versus KCNJ1 and P = 0.014 versus SLC12A1). Deafness at diagnosis was constant in patients with BSND mutations; transient neonatal hyperkalaemia was present in two-thirds of the children with KCNJ1 mutations. Nephrocalcinosis was constant in KCNJ1 and SLC12A1 but not in BSND and CLCNKB patients. In most cases, water/electrolyte supplementation + indomethacin led to catch-up growth. Three patients developed chronic renal failure: one with KCNJ1 mutations during the second decade of age and two with CLCNKB and BSND mutations and without nephrocalcinosis during the first year of life. We confirmed in a large cohort of ante/ neonatal BS that deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. Chronic renal failure is a rare event, associated in this cohort with three genotypes and not always associated with nephrocalcinosis.

Endocochlear potential depends on Cl− channels: mechanism underlying deafness in Bartter syndrome IV

Human Bartter syndrome IV is an autosomal recessive disorder characterized by congenital deafness and severe renal salt and fluid loss. It is caused by mutations in BSND, which encodes barttin, a beta-subunit of ClC-Ka and ClC-Kb chloride channels. Inner-ear-specific disruption of Bsnd in mice now reveals that the positive potential, but not the high potassium concentration, of the scala media depends on the presence of these channels in the epithelium of the stria vascularis. The reduced driving force for K(+)-entry through mechanosensitive channels into sensory hair cells entails a profound congenital hearing loss and subtle vestibular symptoms. Although retaining all cell types and intact tight junctions, the thickness of the stria is reduced early on. Cochlear outer hair cells degenerate over several months. A collapse of endolymphatic space was seen when mice had additionally renal salt and fluid loss due to partial barttin deletion in the kidney. Bsnd(-/-) mice thus demonstrate a novel function of Cl(-) channels in generating the endocochlear potential and reveal the mechanism leading to deafness in human Bartter syndrome IV.

Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness

Background:Bartter syndrome (BS) is a genetic disorder accompanied by hypokalaemic metabolic alkalosis. BS with sensorineural deafness (SND, OMIM602522) is a newly identified phenotype caused by mutations in the BSND gene...

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

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.