Clinical and Genetic Spectrum of Bartter Syndrome Type 3

Splicing Characterization of CLCNKB Variants in Four Patients With Type III Bartter Syndrome

“…Shao et al reported that deletion of the complete CLCNKB gene was the most common variant in Chinese patients with cBS, and the frequency of whole gene deletion was up to 9/28 (32%). Patients who carried the whole CLCNKB gene deletion variant showed an early-onset, severe phenotype with greater urinary salt wasting (Han et al, 2017;Seys et al, 2017;Li et al, 2019). Taken together, our results support that the whole CLCNKB gene deletion may account for a more severe phenotype of patients.…”

The importance of the thick ascending limb of Henle’s loop in renal physiology and pathophysiology

“…The disease may have features of BS (either antenatal or classic) and/or Gitelman syndrome. 66 ClC-K2 deficient mice exhibit salt losing phenotype, with compensatory increased RAAS axis, hypotension, and increased prostaglandin E2 generation; interestingly, the mice show a blunted response to both furosemide and thiazides, indicating a combined defective salt absorption along both TAL and DT. 67 Activating mutations of the CaSR have been associated with hypocalcemia and hypercalciuria, and sometime hypomagnesemia.…”

Analysis ofCLCNKBmutations at dimer‐interface, calcium‐binding site, and pore reveals a variety of functional alterations in ClC‐Kb channel leading to Bartter syndrome

“…Ca 2+ increases the open probability of ClC‐K channels (Gradogna, Babini, Picollo, & Pusch, ; Gradogna, Fenollar‐Ferrer, Forrest, & Pusch, ) by acting on two amino acids (i.e., E261 and D278). In this study, we got interested in two pathological mutations (Seys et al, ) located in close vicinity to the calcium‐binding site (Gradogna et al, ; Gradogna et al, ): A254V (α helix I; c.761C>T, p.Ala254Val) and G465R (α helix O; c.1393G>A, p.Gly465Arg; see Figure b for localization).…”

“…A relatively large number of pathological CLCNKB mutations positioned throughout the whole length of the protein and affecting particularly the pore and dimer interface has been identified (Andrini et al, 2014;Brochard et al, 2009;Keck et al, 2013;Konrad et al, 2000;Lee et al, 2012;Seys et al, 2017;Stolting, Bungert-Plumke, Franzen, & Fahlke, 2015;Yu et al, 2009;see Andrini et al, 2015 for review). Functional studies began to assess the currents generated by several mutants in Xenopus laevis oocytes immediately after the discovery of Barttin (Estevez et al, 2001;Waldegger et al, 2002), an effort that was continued by attempts to describe the functional consequences of CLCNKB mutations (Andrini et al, 2014;Andrini et al, 2015;Cheng, Lo, Chen, Huang, & Lin, 2017;Martinez & Maduke, 2008;Stolting et al, 2015;Yu et al, 2009).…”

“…We focused our efforts on the functional characterization of five pathological CLCNKB mutations at the dimer interface: A204T (c.610G>A, p.Ala204Thr; Garcia Castano et al, 2013;Rodriguez-Soriano, Vallo, Perez de Nanclares, Bilbao, & Castano, 2005;Simon et al, 1997); A210V (c.629C>T, p.Ala210Val; Yu et al, 2009); P216L (c.647C>T, p.Pro216Leu; Lee et al, 2012;S218N (c.653G>A, p.Ser218Asn;Seys et al, 2017); and G219C (c.655G>T, p.Gly219Cys; Seys et al, 2017; see Figure 6b for localization). A second region important for gating and ion selectivity, around α helix N (Dutzler, Campbell, & MacKinnon, 2003;Dutzler et al, 2002) comprised mutations G424R (c.1270G>A, p.Gly424Arg;Seys et al, 2017) and G437R (c.1309G>C, p.Gly437Arg; Lee et al, 2012;see Figure 6 for localization). Mutations in α helix N encountered in ClC-5 (Lourdel et al, 2012) and in ClC-1 (Pusch, 2002) cause modifications in conductance and gating or alter expression.…”