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Shih-hua Lin - One of the best experts on this subject based on the ideXlab platform.
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Functional severity of CLCNKB mutations correlates with phenotypes in patients with classic Bartter's syndrome
The Journal of physiology, 2017Co-Authors: Chihjen Cheng, Jen Chi Chen, Chou Long Huang, Shih-hua LinAbstract:Mutations in CLCNKB gene encoding human voltage-gated chloride ClC-Kb (hClC-Kb) channel cause classic Bartter's syndrome (BS). In contrast to antenatal BS, classic BS manifests highly variable phenotypes. The functional severity of mutant channel has been proposed to explain this phenomenon. Due to difficulties in the expression of hClC-Kb in heterologous expression systems, the functional consequences of mutant channels haven't been thoroughly examined, and the genotype-phenotype association hasn't been established. In this study, we found that hClC-Kb, when expressed in human embryonic kidney (HEK) cells, was unstable due to degradation by proteasome. In-frame fusion of green fluorescent protein (GFP) to the C-terminus of the channel may ameliorate proteasome degradation. Co-expression of barttin increased protein abundance and membrane trafficking of hClC-Kb and markedly increased functional chloride current. We then functionally characterized eighteen missense mutations identified in our classic BS cohort and others using HEK cells expressing hClC-Kb-GFP. Most CLCNKB mutations resulted in marked reduction in protein abundance and chloride current, especially those residing at barttin-binding sites, dimer interface, and selectivity filter. We enrolled classic BS patients carrying homozygous missense mutations with well-described functional consequences and clinical presentations for genotype-phenotype analysis. We found significant correlations of mutant chloride current with the age at diagnosis, plasma chloride concentration, and urine calcium excretion rate. In conclusion, hClC-Kb expression in HEK cells is susceptible to proteasome degradation, and fusion of GFP to the C-terminus of hClC-Kb improves the protein expression. The functional severity of CLCNKB mutation is an important determinant of the phenotype in classic BS. This article is protected by copyright. All rights reserved
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Chronic renal failure in a boy with classic Bartter's syndrome due to a novel mutation in CLCNKB coding for the chloride channel.
European journal of pediatrics, 2008Co-Authors: Chien-ming Lin, Sungsen Yang, Jeng-daw Tsai, Ming-tso Yan, Shih-hua LinAbstract:Background Progressive renal failure in patients with classic Bartter’s syndrome (cBS) due to inactivating mutations in CLCNKB gene is extraordinarily rare.
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intrafamilial phenotype variability in patients with gitelman syndrome having the same mutations in their thiazide sensitive sodium chloride cotransporter
American Journal of Kidney Diseases, 2004Co-Authors: Shih-hua Lin, Nailin Cheng, Yujuei Hsu, Mitchell L HalperinAbstract:Abstract Background: Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter ( NCC ). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. Methods: Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K + ) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. Results: The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS—less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB . Conclusion: Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.
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Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter
American journal of kidney diseases : the official journal of the National Kidney Foundation, 2004Co-Authors: Shih-hua Lin, Nailin Cheng, Yujuei Hsu, Mitchell L HalperinAbstract:Abstract Background: Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter ( NCC ). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. Methods: Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K + ) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. Results: The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS—less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB . Conclusion: Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.
Mitchell L Halperin - One of the best experts on this subject based on the ideXlab platform.
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intrafamilial phenotype variability in patients with gitelman syndrome having the same mutations in their thiazide sensitive sodium chloride cotransporter
American Journal of Kidney Diseases, 2004Co-Authors: Shih-hua Lin, Nailin Cheng, Yujuei Hsu, Mitchell L HalperinAbstract:Abstract Background: Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter ( NCC ). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. Methods: Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K + ) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. Results: The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS—less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB . Conclusion: Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.
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Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter
American journal of kidney diseases : the official journal of the National Kidney Foundation, 2004Co-Authors: Shih-hua Lin, Nailin Cheng, Yujuei Hsu, Mitchell L HalperinAbstract:Abstract Background: Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter ( NCC ). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. Methods: Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K + ) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. Results: The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS—less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB . Conclusion: Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.
Rajesh V Thakker - One of the best experts on this subject based on the ideXlab platform.
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molecular pathology of renal chloride channels in dent s disease and bartter s syndrome
Experimental Nephrology, 2000Co-Authors: Rajesh V ThakkerAbstract:Recent advances in molecular biology have characterised a new class of chloride channels that are referred to as voltage-gated chloride channels (CLCs). To date 9 such CLCs (CLC-1 to CLC-7, CLC-Ka and CLC-Kb which are respectively encoded by the genes CLCN1 to CLCN7, CLCNKa and CLCNKB) have been identified in mammals. Mutations in 2 of these, referred to as CLC-5 and CLC-Kb, have been defined in the hypercalciuric nephrolithiasis disorders of Dent's disease and a form of Bartter's syndrome, respectively. In addition, other forms of Bartter's syndrome have been defined with mutations involving the bumetanide-sensitive sodium-potassium-chloride co-transporter (NKCC2) and the potassium channel ROMK. Finally, mutations of the thiazide-sensitive sodium chloride co-transporter (NCCT) are associated with Gitelman's syndrome, in which hypocalciuria and hypomagnesaemia are notable features. These molecular genetic studies have increased our understanding of the renal tubular mechanisms that regulate mineral homeostasis.
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Chloride channel mutations in hypercalciuric kidney stone disease
Clinical and Experimental Nephrology, 1998Co-Authors: Rajesh V ThakkerAbstract:Recent advances in molecular biology have characterized a new class of chloride channels that are referred to as voltage-gated chloride channels. To date, 9 such voltage-gated chloride channels have been identified in mammals. These are CLC-1 to CLC-7, CLC-Ka, and CLC-Kb, which are encoded by the genes CLCN1 to CLCN7, CLCNKA , and CLCNKB , respectively. Mutations in 2 of these genes, referred to as CLCN5 and CLCNKB , have been defined in the hypercalciuric nephrolithiasis disorders of Dent's disease and a form of Bartter's syndrome, respectively. In addition, other forms of Bartter's syndrome have been defined, with mutations involving the bumetanide-sensitive sodium-potassium-chloride cotransporter (NKCC2) and the potassium channel, ROMK. Finally, mutations of the thiazide-sensitive sodium chloride cotransporter (NCCT) are associated with Gitelman's syndrome, in which hypocalciuria and hypomagnesemia are notable features. These molecular genetic studies have increased our understanding of the renal tubular mechanisms that regulate mineral homeostasis.
Detlef Böckenhauer - One of the best experts on this subject based on the ideXlab platform.
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Bartter and Gitelman syndromes: Questions of class
Pediatric Nephrology, 2020Co-Authors: Martine T. P. Besouw, Robert Kleta, Detlef BöckenhauerAbstract:Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution.
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Co-Existence of Congenital Adrenal Hyperplasia and Bartter Syndrome due to Maternal Uniparental Isodisomy of HSD3B2 and CLCNKB Mutations.
Hormone research in paediatrics, 2020Co-Authors: Dinesh Giri, Detlef Böckenhauer, Charu Deshpande, John C. Achermann, Norman F. Taylor, Gill Rumsby, Henry Morgan, Senthil Senniappan, Michal AjzensztejnAbstract:Introduction: We present a patient with co-existence of 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency and Bartter syndrome, a unique dual combination of opposing pathologies that has not been reported previously in the literature. Case: A female infant (46,XX) born at 34/40 weeks’ gestation, weighing 2.67 kg (−1.54 standard deviation score) to non-consanguineous parents presented on day 4 of life with significant weight loss. Subsequent investigations revealed hyponatraemia, hypochloraemia, metabolic alkalosis, elevated 17-hydroxyprogesterone, ACTH, and renin. Urine steroid profile suggested HSD3B2 deficiency, which was confirmed by the identification of a homozygous HSD3B2 mutation. Due to the persistence of the hypochloraemic and hypokalemic alkalosis, an underlying renal tubulopathy was suspected. Sequence analysis of a targeted tubulopathy gene panel revealed a homozygous deletion in CLCNKB, consistent with Bartter syndrome type 3. The mother was found to be heterozygous for both mutations in HSD3B2 and CLCNKB, and the father was negative for both. Single-nucleotide polymorphism microarray analysis confirmed 2 segments of homozygosity on chromosome 1 of maternal ancestry, encompassing both HSD3B2 and CLCKNB. Discussion: Identification of a homozygous rare mutation in an offspring of non-consanguineous parents should raise suspicion of uniparental disomy, especially if the phenotype is unusual, potentially encompassing more than one disorder. The persistence of hypokalemic alkalosis, the biochemical fingerprint of hyperaldosteronism in a child with a form of CAH in which aldosterone production is severely impaired, challenges our current understanding of mineralocorticoid-mediated effects in the collecting duct.
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Clinical and diagnostic features of Bartter and Gitelman syndromes.
Clinical kidney journal, 2017Co-Authors: Patrick Walsh, Robert Kleta, Yincent Tse, Emma Ashton, Daniela Iancu, Lucy Jenkins, Marc Bienias, William Van't Hoff, Detlef BöckenhauerAbstract:Background: Bartter and Gitelman syndromes are autosomal recessive disorders of renal tubular salt handling. Due to their rarity, limited long-term data are available to inform prognosis and management. / Methods: Long-term longitudinal data were analysed for 45 children with pathogenic variants in SLC12A1 (n = 8), KCNJ1 (n = 8), CLCNKB (n = 17), BSND (n = 2) and SLC12A3 (n = 10) seen at a single centre between 1984 and 2014. Median follow-up was 8.9 [interquartile range (IQR) 0.7–18.1] years. / Results: Polyhydramnios and prematurity were seen in children with SLC12A1 and KCNJ1 mutations. Patients with CLCNKB mutations had the lowest serum potassium and serum magnesium and the highest serum bicarbonate levels. Fractional excretion of chloride was >0.5% in all patients prior to supplementation. Nephrocalcinosis at presentation was present in the majority of patients with SLC12A1 and KCNJ1 mutations, while it was only present in one patient with CLCNKB and not in SLC12A3 or BSND mutations. Growth was impaired, but within the normal range (median height standard deviation score −1.2 at the last follow-up). Impaired estimated glomerular filtration rate (eGFR
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Genetic causes of hypomagnesemia, a clinical overview
Pediatric Nephrology, 2017Co-Authors: Daan H. H. M Viering, Stephen B. Walsh, Jeroen H F De Baaij, Robert Kleta, Detlef BöckenhauerAbstract:Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg^2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg^2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg^2+ by the thick ascending limb of Henle’s loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg^2+ wasting, as evidenced by an inappropriately high fractional Mg^2+ excretion. Familial renal Mg^2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg^2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16 , CLDN19 , CASR , CLCNKB ), Gitelman-like hypomagnesemias ( CLCNKB , SLC12A3 , BSND , KCNJ10 , FYXD2 , HNF1B , PCBD1 ), mitochondrial hypomagnesemias ( SARS2 , MT-TI , Kearns–Sayre syndrome) and other hypomagnesemias ( TRPM6 , CNMM2 , EGF , EGFR , KCNA1 , FAM111A ). Although identification of these genes has not yet changed treatment, which remains Mg^2+ supplementation, it has contributed enormously to our understanding of Mg^2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.
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Genetic causes of hypomagnesemia, a clinical overview
Pediatric Nephrology, 2017Co-Authors: Daan H. H. M Viering, Stephen B. Walsh, Jeroen H F De Baaij, Robert Kleta, Detlef BöckenhauerAbstract:Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg^2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg^2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg^2+ by the thick ascending limb of Henle’s loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg^2+ wasting, as evidenced by an inappropriately high fractional Mg^2+ excretion. Familial renal Mg^2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg^2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16 , CLDN19 , CASR , CLCNKB ), Gitelman-like hypomagnesemias ( CLCNKB , SLC12A3 , BSND , KCNJ10 , FYXD2 , HNF1B , PCBD1 ), mitochondrial hypomagnesemias ( SARS2 , MT-TI , Kearns–Sayre syndrome) and other hypomagnesemias ( TRPM6 , CNMM2 , EGF , EGFR , KCNA1 , FAM111A ). Although identification of these genes has not yet changed treatment, which remains Mg^2+ supplementation, it has contributed enormously to our understanding of Mg^2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.
Yujuei Hsu - One of the best experts on this subject based on the ideXlab platform.
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intrafamilial phenotype variability in patients with gitelman syndrome having the same mutations in their thiazide sensitive sodium chloride cotransporter
American Journal of Kidney Diseases, 2004Co-Authors: Shih-hua Lin, Nailin Cheng, Yujuei Hsu, Mitchell L HalperinAbstract:Abstract Background: Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter ( NCC ). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. Methods: Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K + ) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. Results: The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS—less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB . Conclusion: Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.
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Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter
American journal of kidney diseases : the official journal of the National Kidney Foundation, 2004Co-Authors: Shih-hua Lin, Nailin Cheng, Yujuei Hsu, Mitchell L HalperinAbstract:Abstract Background: Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter ( NCC ). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. Methods: Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K + ) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. Results: The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS—less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB . Conclusion: Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.