Disease relevance of CLCNKB

• RESULTS: The CLCNKB T481S variant showed no association with hypertension [1].
• A Spanish founder mutation in the chloride channel gene, CLCNKB, as a cause of atypical Bartter syndrome in adult age [2].
• Recently, mutations in a basolateral chloride channel CLC-Kb (CLCNKB) have been described in a subset of patients with a Bartter-like phenotype typically lacking nephrocalcinosis [3].
• AMACR expression was highest in papillary RCC, and CLCNKB was highest in chromophobe RCC/oncocytoma [4].
• Classic Bartter syndrome is due to a mutation in the gene encoding the chloride channel (CLCNKB), also a regulator of NKCC2, and typically presents in infancy or early childhood with failure to thrive [5].

High impact information on CLCNKB

• In the absence of barttin, only a small percentage of rClC-K1 and hClC-Kb channels are inserted into the plasma membrane [6].
• We have cloned two closely related putative Cl- channels from both rat kidney (designated rClC-K1 and rClC-K2) and human kidney (hClC-Ka and hClC-Kb) by sequence homology to the ClC family of voltage-gated Cl- channels [7].
• By contrast, we did not detect currents upon hClC-Kb expression in Xenopus oocytes [8].
• Using a chimeric approach, we defined a protein domain that, when replaced by that of rClC-K1, allowed the functional expression of a chimera consisting predominantly of hClC-Kb [8].
• Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome [3].

Chemical compound and disease context of CLCNKB

• Molecular Analysis of the CLCNKB Gene in Japanese Patients with Classic Bartter Syndrome [9].

Biological context of CLCNKB

• Modulation of ClC-Kb chloride channel activity by polymorphic variations of the CLCNKB gene, thus, could form a molecular basis for salt sensitivity of blood pressure regulation [10].
• CONCLUSION: Our data fail to support previous association findings for TNFRSF1B and CLCNKB at the chromosome 1p36 locus implicated in hypertension [1].
• CONCLUSIONS: Our findings demonstrate intrafamilial heterogeneity, namely the presence of GS and CBS phenotypes, in a kindred with the CLCNKB R438H mutation [11].
• Mutation analysis by direct sequencing revealed a novel homozygous missense mutation, arginine 438 to histidine (R438H), in exon 13 of CLCNKB in all patients [11].
• CONCLUSIONS: The present report confirms a weak genotype-phenotype correlation in patients with CLCNKB mutations and supports the founder effect of the A204T mutation in Spain. In our country, the genetic diagnosis of adult patients with hereditary hypokalaemic tubulopathies should include a screening of A204T mutation in the CLCNKB gene [2].

Anatomical context of CLCNKB

• The widespread expression of both ClC-K isoforms in the cochlea may help to explain the symptoms of Bartter's syndrome Type III, a mutation in the hClC-Kb gene (human homologue of ClC-K2), which results in renal salt wasting without deafness [12].

Associations of CLCNKB with chemical compounds

• Assignment of the genes encoding the human chloride channels, CLCNKA and CLCNKB, to 1p36 and of CLCN3 to 4q32-q33 by in situ hybridization [13].
• Inactivation mutations of the luminal thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubules or the basolateral chloride channel (CLCNKB) in the distal nephron are the most common genetic mutations in Gitelman's syndrome (GS) or Bartter's syndrome (BS) [14].
• Classic Bartter's syndrome has been demonstrated to result from defective chloride transport across the basolateral membrane in the distal nephron due to mutations in the chloride channel gene CLCNKB [15].
• All ten patients were found to be homozygous for an identical missense mutation in the CLCNKB gene, substituting a threonine for an alanine at codon 204 (A204T) in the putative fifth transmembrane domain of the protein [16].

Regulatory relationships of CLCNKB

• A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity [10].

Other interactions of CLCNKB

• These were genotyped for TNFRSF1B variants T-1710A upstream, A257G in exon 2, a CA-repeat polymorphism in intron 4, E232K and M196R in exon 6, and T1668G and T1690C in the 3'-untranslated region, and the T481S variant of CLCNKB [1].
• RECENT FINDINGS: Hypercalciuria is discussed relative to mutations in the renal chloride genes CLCN5 and CLCNKB, WNK kinases, ATPB61, and NPT2 [17].
• Linkage analysis in affected patients excluded the TSC gene, SLC12A3, as the mutated gene, but demonstrated linkage to the Cl- channel gene, CLCNKB, on chromosome 1p36 [11].
• Recently, 3 functional polymorphisms, G(-930)A in CYBA, T481S in CLCNKB, and E65K in KCNMB1, were reported to be associated with blood pressure (BP) status and the aim of this study was to confirm those findings using a large cohort representing the general Japanese population [18].
• Importantly, there appears to be a phenotypic difference between subjects with Bartter's syndrome due to CLCKB abnormalities and those with NKCC2 or ROMK1 mutations [19].

Analytical, diagnostic and therapeutic context of CLCNKB

• Molecular analysis included PCR single-strand confirmational polymorphism, direct sequencing of both the NCC and CLCNKB genes, and restriction fragment length polymorphism [14].
• Multivariate analysis gave no support of interaction between the CLC-Kb T481S polymorphism, gender, age or body mass index regarding their effect on BP [20].

References