Analysis of renal tubular electrolyte transporter genes in seven patients with hypokalemic metabolic alkalosis

Fukuyama, Shigeru; Okudaira, Shoko; Yamazato, Syosin; Yamazato, Masahiro; Ohta, Takao

doi:10.1046/j.1523-1755.2003.00163.x

Cited by 44 publications

(37 citation statements)

References 29 publications

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“…Recently, Schlingmann (20) has reported a case with mutations in two genes involved in renal salt transport: a child with renal salt losing tubulopathy and deafness did not show defects on the Barttin gene, but had homozygous mutations on both the ClC-Ka and -Kb chloride channels. Fukuyama et al (21) hypothesized that GS and BS patients frequently show mutations in more than one of the involved transporter genes but, in our view, the patients described in their paper must be considered as polymorphism carriers as Jeck et al (22) subsequently demonstrated that three of the four amino acid variants were common sequence variations without any functional effect in an expression system study. Heterozygote for CLCNKB and SLC12A3 mutations.…”

Section: Discussionmentioning

confidence: 99%

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

Bettinelli¹,

Borsa

Syrén

et al. 2005

Pediatr Res

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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...

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Section: Discussionmentioning

confidence: 99%

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

Bettinelli¹,

Borsa

Syrén

et al. 2005

Pediatr Res

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“…Moreover, this mutation has been reported to be responsible for GS in at least three reports (11−13). Monkawa et al (11) reported that 1 of their 6 subjects with GS (from Tokyo and Tochigi) was heterozygous for this mutation, Fukuyama et al (12) reported that 1 of their 7 GS subjects (from Okinawa) was heterozygous for it, and Maki et al (13) reported that 2 of their 8 GS subjects (from Akita) showed compound heterozygosity for the mutation. This reproducibility further strengthens the hypothesis that the L849H mutation is responsible for GS.…”

Section: Discussionmentioning

confidence: 99%

Functional Confirmation of Gitelman's Syndrome Mutations in Japanese

et al. 2005

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Gitelman's syndrome is an autosomal recessive inherited renal tubular disorder resulting from loss-of-function mutations in the thiazide-sensitive sodium chloride cotransporter gene (SLC12A3). We have previously reported that the combined allele frequency for the reported Gitelman's syndrome mutations is 0.0321. However, almost all of the reported Gitelman's syndrome mutations were from case reports without functional confirmation. In the present study, we assessed the functionality of the two most prevalent mutations in Japanese, T180K and L849H, using a mammalian cell expression system. Human SLC12A3 cDNA was tran-

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“…All exons and exon-intron boundaries of the CLCNKB and SLC12A3 genes were amplified by polymerase chain reaction and direct sequencing using previously described primer pairs. 10,17 Patients suspected to have BS/GS with no CLCNKB or SLC12A3 mutations were diagnosed as having p-BS/GS. If patients suspected to have BS/GS carried only one CLCNKB or SLC12A3 mutant allele, we performed additional semiquantitative polymerase chain reaction 10,18 or multiplex ligation-dependent probe amplification using the SALSA P266-CLCNKB or P136-SLC12A3 multiplex ligation-dependent probe amplification assays (MRC-Holland, Amsterdam, The Netherlands) to detect large heterozygous deletions.…”

Section: Mutational Analysesmentioning

confidence: 99%

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

Matsunoshita

Nozu

Shono

et al. 2016

Genetics in Medicine

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Purpose: Phenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/ GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features. Methods:A total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined. Results:Patients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease.

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Analysis of renal tubular electrolyte transporter genes in seven patients with hypokalemic metabolic alkalosis

Abstract: Our findings demonstrate that in Bartter's and Gitelman's syndromes, it may not be uncommon to see mutations in several causative transporter genes.

Cited by 44 publications

References 29 publications

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

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

Functional Confirmation of Gitelman's Syndrome Mutations in Japanese

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

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