Simultaneous Mutations in the CLCNKB and SLC12A3 Genes in Two Siblings with Phenotypic Heterogeneity in Classic Bartter Syndrome

Abstract

Two siblings (brother and sister) with renal tubular hypokalemic alkalosis underwent clinical, biochemical and molecular investigations. Although the biochemical findings were similar (including hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism and normal blood pressure), the clinical findings were different: the boy, who also presented syndromic signs, developed glomerular proteinuria and renal biopsy revealed focal segmental glomerular sclerosis; the girl showed the typical signs of classic Bartter syndrome. As described in a previous paper, a heterozygous mutation (frameshift 2534delT) was demonstrated in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) of the distal convoluted tubule; the second molecular analysis revealed a compound heterozygous mutation (A61D/V149E) in the CLCNKB chloride channel gene in both subjects, inherited in trans from the parents. The children were finally diagnosed as having classic Bartter syndrome. These cases represent the first report of the simultaneous presence of heterozygous and compound heterozygous mutations in the SLC12A3 and CLCNKB genes, both of which are involved in renal salt losing tubulopathies, and confirm previous observations regarding classic Bartter syndrome phenotype variability in the same kindred. Bartter syndromes are inherited disorders characterized by hypokalemia, metabolic alkalosis, hyperreninemic-hyperaldosteronism and renal salt wasting in the presence of normal blood pressure that have at least three different phenotypes: a) antenatal Bartter syndrome (aBS) [OMIM 241200 and 601678] that is characterized by polyhydramnios, premature delivery, a failure to thrive, hypercalciuria and nephrocalcinosis (1), and may be caused by genetic variants in the genes encoding the luminal Na-K-2Cl co-transporter (2) and the ROMK potassium channel (3); b) the Bartter syndrome associated with sensorineural deafness [OMIM 602522] (4), in which the defects reside in the BSND gene (5); and c) classic Bartter syndrome (cBS) [OMIM 607364] which usually onsets in the first year of life.The main findings in cBS are a failure to thrive and marked salt wasting, and there may be nephrocalcinosis and hypercalciuria (6). The causative mutations are located in the CLCNKB gene encoding the basolateral chloride channel (ClC-Kb) (6,7), which is located in the thick ascending limb of Henle's loop (TAL) and the distal tubule (DCT) (7). The characteristics of cBS are similar to those observed during combined thiazide and furosemide treatments (8).Gitelman syndrome (GS) [OMIM 263800] is a different form of inherited hypokalemic metabolic alkalosis that usually onsets during childhood but may also emerge in adult life (9). It is characterized by hypomagnesemia and hypocalciuria, muscle weakness and tetanic crises, and its phenotype is due to mutations in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) expressed in the DCT (10,11). Unlike cBS, GS resembles the effect of long-term thiazide administration alone (8).The over...

Atypical phenotype of type I Bartter syndrome accompanied by focal segmental glomerulosclerosis

“…Kidney biopsy results were mostly compatible with BS, while the glomerulus showed perihilar sclerosis, which has been reported in cases of BS or Gitelman syndrome (GS) [5][6][7][8][9]. Detection of a compound heterozygous missense mutation in the SLC12A1 gene led to a diagnosis of type I BS.…”

“…b Both amino acid positions are evolutionarily well conserved with BS have shown JGA hyperplasia, interstitial fibrosis, and vascular wall hypercellularity, which were also observed in our patient. The presence of FSGS in patients with BS or GS has been previously reported in five papers (Table 1) [5][6][7][8][9]. Since the FSGS lesion detected in our patient was the perihilar type of adapted FSGS as classified by D'Agati [12], one possible explanation for the presence of FSGS is that stimulation of the renin-angiotensin system (RAS) with increased angiotensin II is involved in the mechanism of sclerosis or that FSGS is the result of chronic hyperfiltration by salt-losing nephropathy associated with type I BS [13].…”

Extending the scope of diagnostic chromosome analysis: Detection of single gene defects using high-resolution SNP microarrays

“…An unaffected sibling did not share this specific LCSH or recombinant thereof, supporting the possibility of a recessive sequence mutation in one of these genes in the proband. Sequence analysis of CLC-NKB revealed a homozygous missense variant (c.446T>A; p.V149E) that has previously been described as pathogenic [Bettinelli et al, 2005].…”

A Thiazide Test for the Diagnosis of Renal Tubular Hypokalemic Disorders

“…As an example, phenotypic overlapping is widely known between patients with mutations in CLCNKB and SLC12A3 genes and between mutations in all BS-causative genes (2,16,28,29). Intrafamilial heterogeneity in phenotypic expression of a same mutation is also well described (29,30). Therefore, precise phenotypic characterization of individual tubular disorders may greatly help restrict the genetic workup; however, traditional parameters, such as age, plasma Mg, and urine Ca excretion, lack specificity.…”