A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes

Abstract

Our findings demonstrate intrafamilial heterogeneity, namely the presence of GS and CBS phenotypes, in a kindred with the CLCNKB R438H mutation. We conclude that GS can be caused by a mutation in a gene other than SLC12A3. The exact role of the CLCNKB R438H mutation in the pathogenesis of the electrolyte and mineral abnormalities in GS and CBS remains to be established.

Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo–Bartter/Gitelman syndrome based on clinical characteristics

“…5,21 By contrast, the clinical manifestations of type III BS and GS may vary and resemble each other. 7,[11][12][13] Furthermore, p-BS/GS is difficult to distinguish from type III BS or GS because its clinical features match those of the latter two diseases. Correctly distinguishing these three diseases based on their clinical characteristics is thus important.…”

“…Some cases of type III BS were previously reported to show features similar to those of GS, including hypomagnesemia and hypocalciuria. 7,[11][12][13] In addition, one report published in 2003 showed that, in a large consanguineous family, both the BS and GS phenotypes were present with the same CLCNKB mutation. 13 In the same year a review article pointed out the phenotypic overlaps between type III BS and GS.…”

“…7,[11][12][13] In addition, one report published in 2003 showed that, in a large consanguineous family, both the BS and GS phenotypes were present with the same CLCNKB mutation. 13 In the same year a review article pointed out the phenotypic overlaps between type III BS and GS. 29 In this study 16.7% of patients with type III BS and 23.3% with p-BS/GS had hypomagnesemia and hypocalciuria, as in GS.…”

“…For example, some patients with type III BS may show clinical features of GS, including hypomagnesemia and hypocalciuria, and diuretic tests may fail to differentiate between them. 7,[11][12][13] Moreover, mutations in known disease-related genes have not been identified in some patients with clinically diagnosed BS/GS. This suggests that some acquired conditions may cause a BS/GS-like disorder, or pseudo-BS/GS (p-BS/GS), associated with loss of sodium or chloride in the urine, stool, or vomitus or with chloride-intake deficiency, resulting in clinical symptoms identical to those of BS/GS.…”

Clinical and Genetic Spectrum of Bartter Syndrome Type 3

“…Twenty-seven of these mutations 4 were previously unknown (Figure 2A and B, Supplementary Tables 1 to 3). Two of the three 5 splice-site mutations disrupt the obligatory consensus donor or acceptor splice site and were 6 considered pathogenic as likely to cause exon skipping and frameshift. The variant at position 7 -6 in the acceptor site of exon 14 is a known rare variant (rs369329893, allele frequency in 8 African populations of 0.02%) for which MaxEntScan predicts a 100% decrease in splice-site 9 score and SpliceSiteFinder predicts activation of an intronic cryptic acceptor site.…”