A novel mutation of CLCNKB in a Japanese patient of Gitelman-like phenotype with diuretic insensitivity to thiazide administration

Ohkubo, Kumiko; Matsuzaki, Tomoe; Yuki, Makiko; Yoshida, Ryoko; Terawaki, Yuichi; Maeyama, Akira; Kawashima, Hiroki; Ono, Junko; Yanase, Toshihiko; Matsunaga, Akira

doi:10.1016/j.mgene.2014.04.005

Cited by 7 publications

(6 citation statements)

References 31 publications

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“…Because patients excrete high levels of PGE2 with the urine and blockers of PGE2 synthesis significantly alleviate the symptoms, this variant is also called the "hyperprostaglandinuria syndrome". 6,[11][12][13][14][15] Finally, mutations in the BSND gene lead to type 4 BS, the most severe form of BS with extreme growth retardation, very severe salt-wasting, and sensorineural deafness. Nevertheless, patients related to CLCNKB show a high phenotypic variability with clinical presentations ranging from very severe salt-losing nephropathy with marked hypokalemia to almost asymptomatic presentation.…”

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confidence: 99%

The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron

Hennings

Andrini

Picard

et al. 2016

JASN

118

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Chloride transport by the renal tubule is critical for blood pressure (BP), acid-base, and potassium homeostasis. Chloride uptake from the urinary fluid is mediated by various apical transporters, whereas basolateral chloride exit is thought to be mediated by ClC-Ka/K1 and ClC-Kb/K2, two chloride channels from the ClC family, or by KCl cotransporters from the SLC12 gene family. Nevertheless, the localization and role of ClC-K channels is not fully resolved. Because inactivating mutations in ClC-Kb/K2 cause Bartter syndrome, a disease that mimics the effects of the loop diuretic furosemide, ClC-Kb/K2 is assumed to have a critical role in salt handling by the thick ascending limb. To dissect the role of this channel in detail, we generated a mouse model with a targeted disruption of the murine ortholog ClC-K2. Mutant mice developed a Bartter syndrome phenotype, characterized by renal salt loss, marked hypokalemia, and metabolic alkalosis. Patch-clamp analysis of tubules isolated from knockout (KO) mice suggested that ClC-K2 is the main basolateral chloride channel in the thick ascending limb and in the aldosterone-sensitive distal nephron. Accordingly, ClC-K2 KO mice did not exhibit the natriuretic response to furosemide and exhibited a severely blunted response to thiazide. We conclude that ClC-Kb/K2 is critical for salt absorption not only by the thick ascending limb, but also by the distal convoluted tubule.

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confidence: 99%

The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron

Hennings

Andrini

Picard

et al. 2016

JASN

118

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“…Among other types of inherited tubulopathies, it comprises the most heterogeneous clinical presentation, as compared to GS phenotypes11). There was a report of a novel missense mutation of CLCNKB in a Japanese patient of Gitelman-like phenotype with diuretic insensitiviry to thiazide administration4). A diuretic test using furosemide and thiazide as well as clinical findings has been used to make a differential diagnosis between BS and GS, but there were some reports that showed the discrepancies between the diuretic test and genotype45).…”

Section: Discussionmentioning

confidence: 99%

“…There was a report of a novel missense mutation of CLCNKB in a Japanese patient of Gitelman-like phenotype with diuretic insensitiviry to thiazide administration4). A diuretic test using furosemide and thiazide as well as clinical findings has been used to make a differential diagnosis between BS and GS, but there were some reports that showed the discrepancies between the diuretic test and genotype45). It is recommended to perform the genetic test to diagnosis the hereditary tubulopathies.…”

Section: Discussionmentioning

confidence: 99%

“…In a cohort study, the Korean pediatric patients with CLCNKB mutations manifested from antenatal BS to mixed Bartter-Gitelman phenotypes3). In other populations, it has been also known that the clinical phenotype in patients with CLCNKB mutations can be highly variable, and clinical overlap of symptoms between BS and Gitelman syndrome (GS) is observed45). These studies suggested that a more clinically relevant classification in hereditary tubulopathies is necessary.…”

Section: Introductionmentioning

confidence: 99%

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A novel mutation ofCLCNKBin a Korean patient of mixed phenotype of Bartter-Gitelman syndrome

et al. 2016

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Bartter syndrome (BS) is an inherited renal tubular disorder characterized by low or normal blood pressure, hypokalemic metabolic alkalosis, and hyperreninemic hyperaldosteronism. Type III BS is caused by loss-of-function mutations in CLCNKB encoding basolateral ClC-Kb. The clinical phenotype of patients with CLCNKB mutations has been known to be highly variable, and cases that are difficult to categorize as type III BS or other hereditary tubulopathies, such as Gitelman syndrome, have been rarely reported. We report a case of a 10-year-old Korean boy with atypical clinical findings caused by a novel CLCNKB mutation. The boy showed intermittent muscle cramps with laboratory findings of hypokalemia, severe hypomagnesemia, and nephrocalcinosis. These findings were not fully compatible with those observed in cases of BS or Gitelman syndrome. The CLCNKB mutation analysis revealed a heterozygous c.139G>A transition in exon 13 [p.Gly(GGG)465Glu(GAG)]. This change is not a known mutation; however, the clinical findings and in silico prediction results indicated that it is the underlying cause of his presentation.

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“…Gitelman syndrome (GS) is an autosomal recessive renal tubular disease, first reported by Gitelman et al in 1966 [ 1 ]. GS is caused by a mutation in the SLC12A3 gene which encodes a thiazide-sensitive sodium chloride cotransporter (NCCT) [ 2 , 3 ]. CLCNKB mutations form the molecular basis of classical Bartter syndrome (cBS) as it encodes chloride channels in the renal tubular basement membrane [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical Characteristics and Gene Mutation Analysis of the Chinese Han Population with Gitelman Syndrome: 3 Case Reports and a Literature Review

Chen

2020

Case Reports in Medicine

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The present study reported clinical characteristics and the results of gene mutation analysis of 3 Chinese patients with Gitelman syndrome (GS). Three patients manifested with normal blood pressure, recurrent hypokalemia, and metabolic alkalosis. Only case 2 had obvious hypomagnesemia. Gene sequencing showed a compound heterozygous mutation in SCL12A3 in case 1 and a homozygous mutation in SCL12A3 in case 2. Heterozygous mutations in SCL12A3 and CLCNKB were found in case 3. Then, the literature was reviewed. The keyword “Gitelman syndrome” was inputted into the PubMed, Wanfang Database, and CNK to search all Chinese patients with GS diagnosed by gene mutations and to extract complete clinical data from December 1998 to 2018. Finally, a total of 124 cases of GS were included. No significant differences in the levels of serum potassium and magnesium were observed among the different gene mutations, and the serum magnesium levels in adults were lower than those of the juvenile. GS with reduced blood magnesium had a serious clinical phenotype. Therefore, GS had a diverse phenotype, and its final diagnosis required genetic profiling. The relationship of gene mutation and clinical phenotype needed further study.

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A novel mutation of CLCNKB in a Japanese patient of Gitelman-like phenotype with diuretic insensitivity to thiazide administration

Cited by 7 publications

References 31 publications

The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron

The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron

A novel mutation ofCLCNKBin a Korean patient of mixed phenotype of Bartter-Gitelman syndrome

Clinical Characteristics and Gene Mutation Analysis of the Chinese Han Population with Gitelman Syndrome: 3 Case Reports and a Literature Review

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