RARE DISEASE
Bartter syndrome
Bartter syndrome
Bartter syndrome
Synonyms: Renal tubular normotensive hypokalemic alkalosis with hypercalciuria, Salt-losing tubular disorder, Henle's loop type, Salt-wasting tubulopathy, Henle's loop type
Synonyms: Renal tubular normotensive hypokalemic alkalosis with hypercalciuria, Salt-losing tubular disorder, Henle's loop type, Salt-wasting tubulopathy, Henle's loop type
Synonyms: Renal tubular normotensive hypokalemic alkalosis with hypercalciuria, Salt-losing tubular disorder, Henle's loop type, Salt-wasting tubulopathy, Henle's loop type
Drug discovery
404
papers
On emerging therapies
Overview
Bartter syndrome is an autosomal recessive renal tubulopathy impairing sodium reabsorption in the thick ascending limb of Henle’s loop, causing hypokalemic alkalosis, polyuria, salt wasting, and hyperreninemic hyperaldosteronism. It presents variably, ranging from antenatal polyhydramnios and failure to thrive to childhood/adult-onset muscle weakness and growth retardation [1][2][16]. Genetic variants (types I–V) correlate with clinical severity and complications like nephrocalcinosis [18][19].
Burden
Growth impairment: 41% experience short stature despite therapy [4][12]
Chronic kidney disease: 11% progress to CKD stages 3–5, linked to nephrocalcinosis/prematurity [4][7]
Lifelong management: Frequent electrolyte monitoring, risk of acute decompensation during illness, and reduced quality of life [4][16][18]
Therapies
Electrolyte replacement: High-dose potassium (1–3 mEq/kg/day), sodium (5–10 mEq/kg/day), and magnesium supplements [1][3][16]
NSAIDs: Indomethacin/ibuprofen to reduce prostaglandin-mediated salt wasting; COX-2 inhibitors (e.g., celecoxib) as alternatives [1][3][4]
Adjunctive therapies: Potassium-sparing diuretics, ACE inhibitors (limited evidence); growth hormone for short stature [4][12][18]
Categories: rare genetic diseases, rare renal diseases
Research Papers
404 drug discovery papers about Bartter syndrome. Recent publications:
404 drug discovery papers about Bartter syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-09-13 | CYP4F22-Related Autosomal Recessive Congenital Ichthyosis Associated With Hirschsprung Disease and Bartter-Like Renal Manifestations.
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of inherited cornification disorders caused by defects in epidermal barrier formation. Mutations in CYP4F22 are an uncommon cause of ARCI and are associated with variable phenotypes including lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). This is a report of a genetically confirmed case of CYP4F22-related ARCI in a child born to consanguineous parents who presented with collodion membrane at birth followed by persistent ichthyosiform scaling and palmoplantar keratoderma. Genetic analysis identified a homozygous pathogenic CYP4F22 variant, c.1303C>T p.(His435Tyr). In addition to cutaneous findings, the patient had Hirschsprung disease managed surgically during infancy and was followed by pediatric nephrology for Bartter-like manifestations associated with hypokalemia and bilateral renal stones. This case highlights the importance of recognizing phenotypic heterogeneity of CYP4F22-associated ARCI and describes unusual extracutaneous manifestations in association with this rare genodermatosis.
2026-07-01 | Longest surviving patient with a homozygous splice-altering EGFR pathogenic variant presenting with skin autoinflammation and a Bartter-like salt-losing tubulopathy.
Bartter syndrome (BS) is a salt-losing renal tubulopathy classically characterised by hypokalaemic metabolic alkalosis and hyperreninaemic hyperaldosteronism. We investigated the genetic cause of a Bartter-like phenotype in an adolescent patient with progressive nephrocalcinosis, hypercalciuria, polyuria, metabolic alkalosis, hypokalaemia, significantly elevated urine chloride, failure to thrive, and a salt-losing tubulopathy. Additionally, the patient presented with hypergammaglobulinaemia, abnormal cerebral white matter signal changes, skin autoinflammation, and mild intellectual disability. No pathogenic variants were detected in known BS-related genes, and all recessive BS genes were outside regions of homozygosity (ROH) in this patient from a consanguineous family. Instead, exome sequencing and homozygosity mapping identified a homozygous splicing variant, c.2702-2A>G, in the epidermal growth factor receptor (EGFR) gene within an ~28 Mb ROH on chromosome 7p. RNA-Seq and RT-PCR analysis of the patient's RNA confirmed the pathogenicity of this variant, demonstrating aberrant splicing resulting in an in-frame retention of 27 nucleotides from intron 22 of EGFR. Immunofluorescence analysis of the proband's skin revealed a reduced EGFR protein level, rather than a complete absence, supporting a hypomorphic effect and likely explaining compatibility with survival into adolescence. Whereas previously reported EGFR variants have been associated with severe neonatal epithelial inflammation, bowel disease, and early mortality, our findings demonstrate that a hypomorphic variant can be compatible with survival into the second decade of life. These findings support an association between a syndromic Bartter-like salt-losing tubulopathy with epithelial autoinflammation and a homozygous splice-altering EGFR pathogenic variant, thereby expanding the phenotypic spectrum of EGFR-associated disorders.
2026-06-19 | Suspected Bartter syndrome in 22-year-old male: a case report
Background. Hypokalemia can result from inadequate potassium intake or excessive potassium loss through renal or extrarenal routes. In patients with renal potassium wasting, normotension, and metabolic alkalosis, the main differential diagnoses include renal tubular disorders, particularly Bartter syndrome and Gitelman syndrome. These inherited disorders are caused by genetic mutations that impair renal salt reabsorption; therefore, genetic testing is required to establish a definitive diagnosis. Case description. We present the case of a 22-year-old male with hypokalemia, normotension, and metabolic alkalosis who was suspected of having Bartter syndrome. He had bilateral lower limb weakness without other complaints. Laboratory investigations revealed severe hypokalemia (serum potassium, 1.96 mEq/L), increased urinary potassium (130 mmol/24 h), sodium (280 mmol/24 h), and chloride excretion (310 mmol/24 h), normal urinary calcium excretion (150 mg/24 h), and metabolic alkalosis (pH 7.48, PaCO₂ 45 mmHg, HCO₃⁻ 30 mEq/L). Intravenous potassium chloride was administered, resulting in an increase in serum potassium to 2.7 mEq/L the following day. Subsequent oral potassium supplementation failed to produce further improvement, and serum potassium remained at 2.7 mEq/L until discharge. Nevertheless, the patient’s muscle strength improved during hospitalization. Conclusion. Bartter syndrome should be considered in patients presenting with normotensive hypokalemic metabolic alkalosis; however, a definitive diagnosis requires genetic testing demonstrating pathogenic mutations in renal tubular transporters, cotransporters, or ion channels.
2026-06-11 | A Rare Case of Bartter Syndrome Type 3 Diagnosed in Elderly Age.
Bartter syndrome (BS) type 3 typically presents in childhood and is caused by defects in NaCl transporters of the thick ascending limb of the loop of Henle. We report a 66-year-old woman with asymptomatic but severe hypokalemia (2.0 mmol/L), metabolic alkalosis, and hyperreninemic hyperaldosteronism. Initial clinic blood pressure was 157/88 mmHg, but repeated office and home measurements were ~120/70 mmHg, consistent with white-coat hypertension. Imaging excluded renovascular disease. Sequential diuretic testing supported BS physiology: a thiazide loading test increased fractional excretion of chloride (FECl) from 0.46% to 3.88% (ΔFECl 3.4%), exceeding the 2.3% cutoff that argues against Gitelman syndrome; a furosemide test showed chloride reabsorption of 10.1%, indicating a profound loop-segment defect, even lower than values commonly reported in BS3. Targeted next-generation sequencing identified a homozygous CLCNKB stop-gain variant (c.1830G >A; p.Trp610Ter), confirming BS type 3. High-dose potassium chloride (9.9 g/day) failed to correct hypokalemia, whereas low-dose enalapril plus spironolactone normalized serum potassium (4.0 mmol/L) without persistent hypotension. The urine calcium/creatinine ratio was borderline-normal (0.65 mmol/mmol), rather than hypocalciuric. This case suggests that BS3 should remain in the differential diagnosis of refractory hypokalemia in older adults and highlights the diagnostic value of physiology-guided diuretic testing combined with genetic analysis, as well as the potential efficacy of low-dose ACE inhibitor plus mineralocorticoid receptor antagonist therapy when potassium supplementation alone is insufficient.
2026-04-27 | Molecular Genetics of Bartter Syndrome: Bridging Genotype-Phenotype Correlations and Precision Therapeutics.
Bartter syndrome (BS) represents a group of rare, autosomal recessive renal tubular disorders characterized by hypokalemic hypochloremic metabolic alkalosis, secondary hyperaldosteronism, and normal to low blood pressure. The underlying pathophysiology is primarily driven by defects in critical ion transport proteins or channels localized within the thick ascending limb of the loop of Henle, leading to impaired salt reabsorption. Recent advances in molecular genetics have refined the classification of Bartter syndrome. Current evidence supports SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 as the core disease genes within the contemporary BS spectrum, with MAGED2 causing a distinct X-linked transient antenatal form. In contrast, gain-of-function CASR variants, historically labeled "type V Bartter syndrome", are now more appropriately described as CaSR-associated Bartter-like phenotypes within the broader spectrum of disorders of calcium homeostasis. Despite significant progress, two primary research limitations remain. First, fully elucidating genotype-phenotype correlations and overcoming diagnostic complexities continues to be highly challenging due to substantial phenotypic overlap and genetic heterogeneity. Compounding these diagnostic hurdles is the equally critical challenge of understanding mutation-driven pathogenic mechanisms to develop viable clinical interventions. This review systematically summarizes the current molecular genetic landscape of BS to address these gaps. We highlight the relationships between specific genetic variants and clinical manifestations, delve into molecular pathophysiology including protein misfolding and trafficking defects, and explore emerging therapeutic approaches such as molecular chaperones. By integrating genetic and clinical data, this work aims to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome.
proteins
2026-08-20 | Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice.
The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased salt reabsorption in the thick ascending limb of Henle's loop (TAL). By studying Clc-k2 (mouse ortholog of ClC-Kb)-knockout (Clc-k2-/-) mice, we recently uncovered an additional mechanism in which loss of Clc-k2 induces TAL hypoplasia in neonatal kidneys, exacerbating BS severity. Here, we further investigated this mechanism. TALs and distal convoluted tubules (DCTs) isolated from Clc-k2-/- and wild-type mice were used for transcriptome, proteomics, cell cycle, and proliferation assays. Mitochondrial morphology and function were studied using electron microscopy and mitochondrial respiration assays. Our results revealed impairments in cell proliferation, S-to-G2/M cell cycle transition, mitochondrial biogenesis, oxidative phosphorylation, glycolysis, and fatty acid oxidation in Clc-k2-/- TALs and DCTs. Increasing transport function by introducing a gain-of-function with-no-lysine kinase 4 mutation in Clc-k2-/- mice restored these metabolic and proliferative impairments and improved phenotype. Transgenic expression of peroxisome proliferator-activated receptor gamma coactivator-1α, a master regulator of mitochondrial biogenesis, in Clc-k2-/- mice also alleviated mitochondrial dysfunction and phenotype. These findings support the hypothesis that mitochondrial hypofunction, resulting from decreased transport function, contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a potential therapeutic approach for BS.
2026-03-01 | Identification of compound heterozygous LRBA variants associated with Pneumocystis jirovecii pneumonia and toxoplasmosis
Background: Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM #614700. The LRBA protein is crucial for immune regulation, receptor recycling, and autophagy. LRBA deficiency is linked to various clinical manifestations, including autoimmunity, lymphoproliferation, and humoral immune deficiency. Aim: To describe the clinical course and diagnosis of a patient identified with LRBA deficiency. Methods: A thorough review of the patient’s medical chart was performed. Results: We report the case of a 42-year-old female born prematurely and diagnosed with Bartter syndrome, with features of immune dysregulation presenting during childhood, manifesting as recurrent bacterial and viral sinopulmonary infections, lymphadenopathy, pancytopenia, and atopy. Her clinical status deteriorated in adulthood with multi-organ involvement, including granulomatous lymphocytic interstitial lung disease, progressive hepatosplenomegaly with resultant portal hypertension; acute on chronic kidney disease with nephrocalcinosis; and severe immune dysfunction characterized by low T and B cells, recurrent bacterial, fungal and viral infections and susceptibility to opportunistic infections including Candida, Pneumocystis jirovecii and Toxoplasma gondii. Research-based analysis of the patient’s clinical exome identified two variants in the LRBA gene, a rare missense c.6697G>A (p. Ala2233Thr) change and a novel intronic splice site c.4005-210G>C (p.?) change strengthening the acceptor splice site of a pseudo-exon, classified as variants of unknown significance. In addition to her genetic findings pertaining to Bartter syndrome (SLC12A1: c.596G>A [p. Arg199His], and c.1543 G>T [p. Ala515Ser]), a heterozygous variant of uncertain significance in NOD2, c.866A>G (p. Asn289Ser), was identified. A positive pathogenic heterozygous mutation in DOCK8 was also found, although follow-up functional testing for DOCK8 expression did not confirm a DOCK8 deficiency, with adequate expression of DOCK8 protein in T and NK cells. Based on the LRBA genetic variants identified by exome sequencing, add-on therapy with abatacept, a recombinant cytotoxic T lymphocyte-associated protein 4 (CTLA4) fusion protein, was initiated as a targeted therapy for LRBA deficiency. Conclusion: This case expands our knowledge of the clinical manifestations of LRBA deficiency and the potential associations across the spectrum of immune dysregulation. Early incorporation of genetic sequencing into the diagnostic evaluation, may play a beneficial role in early diagnosis and treatment, particularly in individuals at risk for life-threatening immunodeficiencies and rare disorders. Statement of novelty: We report the diagnostic journey of a patient with compound heterozygous variants in the LRBA gene, along with findings of a NOD2 variant and her known diagnosis of Bartter syndrome. Identifying the variants in LRBA enabled the use of targeted therapies, which have demonstrated clinical and multi-organ benefits in affected individuals.
2024-10-01 | Unraveling the Role of Mitochondrial Dysfunction in the Pathogenesis of Clc-k2-Deficient Bartter Syndrome Mice
Background: Mutations in human ClC-Kb (Clc-k2 in mice) lead to Bartter syndrome (BS) type 3, a congenital renal tubulopathy. Our previous research showed the constitutive deletion of Clc-k2 in mouse kidneys hindered the postnatal development of thick ascending limbs (TALs) through mechanisms not yet fully understood. Our recent extracellular flux analysis revealed that low transport activity in renal tubules resulted in low mitochondrial mass and respiratory capacity. This alarming discovery prompted us to delve deeper into the mitochondrial functions in Clc-k2-deficient TALs and explore the potential of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), the master activator of mitochondrial biogenesis, in rescuing Bartter syndrome. Methods: We analyzed the mitochondrial biogenesis and bioenergetics in isolated TALs using mitochondrial DNA copy numbers, seahorse-based mitochondrial assays, and electron microscopy. We also conducted a comparative transcriptome analysis using isolated Clc-k2 KO vs. wild-type TALs. Uromodulin-positive TAL/DCT cells were pulled down and used for cell cycle and proliferation assays. Pseudohypoaldosteronism type 2 (PHA2) WNK4D561A/+ mutant knockin mice and PGC1-α transgenic mice were crossed with Clc-k2 KO mice to rescue the transport activity/mitochondrial function, respectively. Mouse phenotypes then analyzed and compared. Results: Clc-k2-deficient TALs had reduced mitochondrial-to-nuclear DNA ratio and mitochondrial respiratory capacities, indicating downregulated mitochondrial biogenesis and bioenergetics. Transcriptome analysis confirmed suppression of mitochondrial genes in Clc-k2-deficient TALs. These cells were prone to G1-S cell cycle transition and proliferation delay. PHA2 WNK4D561A/+ mutant improved the mitochondrial mass/function, cell cycle, and proliferation of Clc-k2-deficient TAL cells and rescued the activity of NKCC2 and NCC cotransporter of Clc-k2-deficient mice. Overexpression of PGC1-α in Clc-k2 KO mice improved mitochondrial function of TAL, NKCC2/NCC activities, and BS phenotype. Conclusion: Our results support that low transport activity suppresses mitochondrial biogenesis/bioenergetics in renal tubules, thereby aggravating renal salt wasting, cell cycle delay, and TAL hypoplasia in Clc-k2-deficient BS mice. Mitochondrial-targeting therapy could be promising to BS. Funding: Other NIH Support - R01
2024-08-31 | Regulation of ClC-K/barttin by endocytosis influences distal convoluted tubule hyperplasia.
ClC-K/barttin channels are involved in the transepithelial transport of chloride in the kidney and inner ear. Their physiological role is crucial in humans because mutations in CLCNKB or BSND, encoding ClC-Kb and barttin, cause Bartter's syndrome types III and IV, respectively. In vitro experiments have shown that an amino acid change in a proline-tyrosine motif in the C-terminus of barttin stimulates ClC-K currents. The molecular mechanism of this enhancement and whether this potentiation has any in vivo relevance remains unknown. We performed electrophysiological and biochemical experiments in Xenopus oocytes and kidney cells co-expressing ClC-K and barttin constructs. We demonstrated that barttin possesses a YxxØ motif and, when mutated, increases ClC-K plasma membrane stability, resulting in larger currents. To address the impact of mutating this motif in kidney physiology, we generated a knock-in mouse. Comparing wild-type (WT) and knock-in mice under a standard diet, we could not observe any difference in ClC-K and barttin protein levels or localization, either in urinary or plasma parameters. However, under a high-sodium low-potassium diet, known to induce hyperplasia of distal convoluted tubules, knock-in mice exhibit reduced hyperplasia compared to WT mice. In summary, our in vitro and in vivo studies demonstrate that the previously identified PY motif is indeed an endocytic YxxØ motif in which mutations cause a gain of function of the channel. KEY POINTS: It is revealed by mutagenesis and functional experiments that a previously identified proline-tyrosine motif regulating ClC-K plasma membrane levels is indeed an endocytic YxxØ motif. Biochemical characterization of mutants in the YxxØ motif in Xenopus oocytes and human embryonic kidney cells indicates that mutants showed increased plasma membrane levels as a result of an increased stability, resulting in higher function of ClC-K channels. Mutation of this motif does not affect barttin protein expression and subcellular localization in vivo. Knock-in mice with a mutation in this motif, under conditions of a high-sodium low-potassium diet, exhibit less hyperplasia in the distal convoluted tubule than wild-type animals, indicating a gain of function of the channel in vivo.
2019-08-13 | A novel CLCNKB mutation in a Chinese girl with classic Bartter syndrome: a case report
Bartter syndrome (BS) is a rare autosomal recessive disorder of salt reabsorption at the thick ascending limb of the Henle loop, characterized by hypokalemia, salt loss, metabolic alkalosis, hyperreninemic hyperaldosteronism with normal blood pressure. BS type III, often known as classic BS (CBS), is caused by loss-of-function mutations in CLCNKB (chloride voltage-gated channel Kb) encoding basolateral ClC-Kb. We reported a 15-year-old CBS patient with a compound heterozygous mutation of CLCNKB gene. She first presented with vomiting, hypokalemic metabolic alkalosis at the age of 4 months, and was clinically diagnosed as CBS. Indomethacin, spironolactone and oral potassium were started from then. During follow-up, the serum electrolyte levels were generally normal, but the patient showed failure to thrive and growth hormone (GH) deficiency was diagnosed. The recombinant human GH therapy was performed, and the growth velocity was improved. When she was 14, severe proteinuria and chronic kidney disease (CKD) were developed. Renal biopsy showed focal segmental glomerulosclerosis (FSGS) with juxtaglomerular apparatus cell hyperplasia, and genetic testing revealed a point deletion of c.1696delG (p. Glu566fs) and a fragment deletion of exon 2–3 deletions in CLCNKB gene. Apart from the CBS, ostium secundum atrial septal defect (ASD) was diagnosed by echocardiography. This is the first report of this compound heterozygous of CLCNKB gene in BS Children. Our findings contribute to a growing list of CLCNKB mutations associated with CBS. Some recessive mutations can induce CBS in combination with other mutations.
gene therapies
2026-01-01 | Epigenetic Reprogramming of Renal Pendrin Expression via CRISPR-dCas9-
Bartter Syndrome Type III, consequent to biallelic loss-of-function mutations in CLCNKB, remains incurable despite six decades of palliative pharmacotherapy. The syndrome is characterized by profound metabolic alkalosis (arterial pH 7.51–7.58), hypochloremia (serum Cl⁻ 82– 88 mEq/L), and hypokalemia, arising from impaired chloride reabsorption in the thick ascending limb. Current regimens—non-selective cyclooxygenase inhibition, potassium-sparing diuretics, and electrolyte supplementation—fail to restore physiological acid-base equilibrium, are complicated by nephrotoxicity and growth failure, and do not address the fundamental molecular lesion. Pendrin (SLC26A4), an apical Cl⁻/HCO₃⁻ exchanger expressed in renal β-intercalated cells, constitutes an endogenous bicarbonate secretory pathway that remains epigenetically silenced in Bartter syndrome despite persistent hypochloremic stimuli.
small molecules
2026-09-13 | CYP4F22-Related Autosomal Recessive Congenital Ichthyosis Associated With Hirschsprung Disease and Bartter-Like Renal Manifestations.
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of inherited cornification disorders caused by defects in epidermal barrier formation. Mutations in CYP4F22 are an uncommon cause of ARCI and are associated with variable phenotypes including lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). This is a report of a genetically confirmed case of CYP4F22-related ARCI in a child born to consanguineous parents who presented with collodion membrane at birth followed by persistent ichthyosiform scaling and palmoplantar keratoderma. Genetic analysis identified a homozygous pathogenic CYP4F22 variant, c.1303C>T p.(His435Tyr). In addition to cutaneous findings, the patient had Hirschsprung disease managed surgically during infancy and was followed by pediatric nephrology for Bartter-like manifestations associated with hypokalemia and bilateral renal stones. This case highlights the importance of recognizing phenotypic heterogeneity of CYP4F22-associated ARCI and describes unusual extracutaneous manifestations in association with this rare genodermatosis.
2026-07-01 | Longest surviving patient with a homozygous splice-altering EGFR pathogenic variant presenting with skin autoinflammation and a Bartter-like salt-losing tubulopathy.
Bartter syndrome (BS) is a salt-losing renal tubulopathy classically characterised by hypokalaemic metabolic alkalosis and hyperreninaemic hyperaldosteronism. We investigated the genetic cause of a Bartter-like phenotype in an adolescent patient with progressive nephrocalcinosis, hypercalciuria, polyuria, metabolic alkalosis, hypokalaemia, significantly elevated urine chloride, failure to thrive, and a salt-losing tubulopathy. Additionally, the patient presented with hypergammaglobulinaemia, abnormal cerebral white matter signal changes, skin autoinflammation, and mild intellectual disability. No pathogenic variants were detected in known BS-related genes, and all recessive BS genes were outside regions of homozygosity (ROH) in this patient from a consanguineous family. Instead, exome sequencing and homozygosity mapping identified a homozygous splicing variant, c.2702-2A>G, in the epidermal growth factor receptor (EGFR) gene within an ~28 Mb ROH on chromosome 7p. RNA-Seq and RT-PCR analysis of the patient's RNA confirmed the pathogenicity of this variant, demonstrating aberrant splicing resulting in an in-frame retention of 27 nucleotides from intron 22 of EGFR. Immunofluorescence analysis of the proband's skin revealed a reduced EGFR protein level, rather than a complete absence, supporting a hypomorphic effect and likely explaining compatibility with survival into adolescence. Whereas previously reported EGFR variants have been associated with severe neonatal epithelial inflammation, bowel disease, and early mortality, our findings demonstrate that a hypomorphic variant can be compatible with survival into the second decade of life. These findings support an association between a syndromic Bartter-like salt-losing tubulopathy with epithelial autoinflammation and a homozygous splice-altering EGFR pathogenic variant, thereby expanding the phenotypic spectrum of EGFR-associated disorders.
2026-06-19 | Suspected Bartter syndrome in 22-year-old male: a case report
Background. Hypokalemia can result from inadequate potassium intake or excessive potassium loss through renal or extrarenal routes. In patients with renal potassium wasting, normotension, and metabolic alkalosis, the main differential diagnoses include renal tubular disorders, particularly Bartter syndrome and Gitelman syndrome. These inherited disorders are caused by genetic mutations that impair renal salt reabsorption; therefore, genetic testing is required to establish a definitive diagnosis. Case description. We present the case of a 22-year-old male with hypokalemia, normotension, and metabolic alkalosis who was suspected of having Bartter syndrome. He had bilateral lower limb weakness without other complaints. Laboratory investigations revealed severe hypokalemia (serum potassium, 1.96 mEq/L), increased urinary potassium (130 mmol/24 h), sodium (280 mmol/24 h), and chloride excretion (310 mmol/24 h), normal urinary calcium excretion (150 mg/24 h), and metabolic alkalosis (pH 7.48, PaCO₂ 45 mmHg, HCO₃⁻ 30 mEq/L). Intravenous potassium chloride was administered, resulting in an increase in serum potassium to 2.7 mEq/L the following day. Subsequent oral potassium supplementation failed to produce further improvement, and serum potassium remained at 2.7 mEq/L until discharge. Nevertheless, the patient’s muscle strength improved during hospitalization. Conclusion. Bartter syndrome should be considered in patients presenting with normotensive hypokalemic metabolic alkalosis; however, a definitive diagnosis requires genetic testing demonstrating pathogenic mutations in renal tubular transporters, cotransporters, or ion channels.
2026-06-11 | A Rare Case of Bartter Syndrome Type 3 Diagnosed in Elderly Age.
Bartter syndrome (BS) type 3 typically presents in childhood and is caused by defects in NaCl transporters of the thick ascending limb of the loop of Henle. We report a 66-year-old woman with asymptomatic but severe hypokalemia (2.0 mmol/L), metabolic alkalosis, and hyperreninemic hyperaldosteronism. Initial clinic blood pressure was 157/88 mmHg, but repeated office and home measurements were ~120/70 mmHg, consistent with white-coat hypertension. Imaging excluded renovascular disease. Sequential diuretic testing supported BS physiology: a thiazide loading test increased fractional excretion of chloride (FECl) from 0.46% to 3.88% (ΔFECl 3.4%), exceeding the 2.3% cutoff that argues against Gitelman syndrome; a furosemide test showed chloride reabsorption of 10.1%, indicating a profound loop-segment defect, even lower than values commonly reported in BS3. Targeted next-generation sequencing identified a homozygous CLCNKB stop-gain variant (c.1830G >A; p.Trp610Ter), confirming BS type 3. High-dose potassium chloride (9.9 g/day) failed to correct hypokalemia, whereas low-dose enalapril plus spironolactone normalized serum potassium (4.0 mmol/L) without persistent hypotension. The urine calcium/creatinine ratio was borderline-normal (0.65 mmol/mmol), rather than hypocalciuric. This case suggests that BS3 should remain in the differential diagnosis of refractory hypokalemia in older adults and highlights the diagnostic value of physiology-guided diuretic testing combined with genetic analysis, as well as the potential efficacy of low-dose ACE inhibitor plus mineralocorticoid receptor antagonist therapy when potassium supplementation alone is insufficient.
2026-04-27 | Molecular Genetics of Bartter Syndrome: Bridging Genotype-Phenotype Correlations and Precision Therapeutics.
Bartter syndrome (BS) represents a group of rare, autosomal recessive renal tubular disorders characterized by hypokalemic hypochloremic metabolic alkalosis, secondary hyperaldosteronism, and normal to low blood pressure. The underlying pathophysiology is primarily driven by defects in critical ion transport proteins or channels localized within the thick ascending limb of the loop of Henle, leading to impaired salt reabsorption. Recent advances in molecular genetics have refined the classification of Bartter syndrome. Current evidence supports SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 as the core disease genes within the contemporary BS spectrum, with MAGED2 causing a distinct X-linked transient antenatal form. In contrast, gain-of-function CASR variants, historically labeled "type V Bartter syndrome", are now more appropriately described as CaSR-associated Bartter-like phenotypes within the broader spectrum of disorders of calcium homeostasis. Despite significant progress, two primary research limitations remain. First, fully elucidating genotype-phenotype correlations and overcoming diagnostic complexities continues to be highly challenging due to substantial phenotypic overlap and genetic heterogeneity. Compounding these diagnostic hurdles is the equally critical challenge of understanding mutation-driven pathogenic mechanisms to develop viable clinical interventions. This review systematically summarizes the current molecular genetic landscape of BS to address these gaps. We highlight the relationships between specific genetic variants and clinical manifestations, delve into molecular pathophysiology including protein misfolding and trafficking defects, and explore emerging therapeutic approaches such as molecular chaperones. By integrating genetic and clinical data, this work aims to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome.
proteins
2026-08-20 | Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice.
The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased salt reabsorption in the thick ascending limb of Henle's loop (TAL). By studying Clc-k2 (mouse ortholog of ClC-Kb)-knockout (Clc-k2-/-) mice, we recently uncovered an additional mechanism in which loss of Clc-k2 induces TAL hypoplasia in neonatal kidneys, exacerbating BS severity. Here, we further investigated this mechanism. TALs and distal convoluted tubules (DCTs) isolated from Clc-k2-/- and wild-type mice were used for transcriptome, proteomics, cell cycle, and proliferation assays. Mitochondrial morphology and function were studied using electron microscopy and mitochondrial respiration assays. Our results revealed impairments in cell proliferation, S-to-G2/M cell cycle transition, mitochondrial biogenesis, oxidative phosphorylation, glycolysis, and fatty acid oxidation in Clc-k2-/- TALs and DCTs. Increasing transport function by introducing a gain-of-function with-no-lysine kinase 4 mutation in Clc-k2-/- mice restored these metabolic and proliferative impairments and improved phenotype. Transgenic expression of peroxisome proliferator-activated receptor gamma coactivator-1α, a master regulator of mitochondrial biogenesis, in Clc-k2-/- mice also alleviated mitochondrial dysfunction and phenotype. These findings support the hypothesis that mitochondrial hypofunction, resulting from decreased transport function, contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a potential therapeutic approach for BS.
2026-03-01 | Identification of compound heterozygous LRBA variants associated with Pneumocystis jirovecii pneumonia and toxoplasmosis
Background: Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM #614700. The LRBA protein is crucial for immune regulation, receptor recycling, and autophagy. LRBA deficiency is linked to various clinical manifestations, including autoimmunity, lymphoproliferation, and humoral immune deficiency. Aim: To describe the clinical course and diagnosis of a patient identified with LRBA deficiency. Methods: A thorough review of the patient’s medical chart was performed. Results: We report the case of a 42-year-old female born prematurely and diagnosed with Bartter syndrome, with features of immune dysregulation presenting during childhood, manifesting as recurrent bacterial and viral sinopulmonary infections, lymphadenopathy, pancytopenia, and atopy. Her clinical status deteriorated in adulthood with multi-organ involvement, including granulomatous lymphocytic interstitial lung disease, progressive hepatosplenomegaly with resultant portal hypertension; acute on chronic kidney disease with nephrocalcinosis; and severe immune dysfunction characterized by low T and B cells, recurrent bacterial, fungal and viral infections and susceptibility to opportunistic infections including Candida, Pneumocystis jirovecii and Toxoplasma gondii. Research-based analysis of the patient’s clinical exome identified two variants in the LRBA gene, a rare missense c.6697G>A (p. Ala2233Thr) change and a novel intronic splice site c.4005-210G>C (p.?) change strengthening the acceptor splice site of a pseudo-exon, classified as variants of unknown significance. In addition to her genetic findings pertaining to Bartter syndrome (SLC12A1: c.596G>A [p. Arg199His], and c.1543 G>T [p. Ala515Ser]), a heterozygous variant of uncertain significance in NOD2, c.866A>G (p. Asn289Ser), was identified. A positive pathogenic heterozygous mutation in DOCK8 was also found, although follow-up functional testing for DOCK8 expression did not confirm a DOCK8 deficiency, with adequate expression of DOCK8 protein in T and NK cells. Based on the LRBA genetic variants identified by exome sequencing, add-on therapy with abatacept, a recombinant cytotoxic T lymphocyte-associated protein 4 (CTLA4) fusion protein, was initiated as a targeted therapy for LRBA deficiency. Conclusion: This case expands our knowledge of the clinical manifestations of LRBA deficiency and the potential associations across the spectrum of immune dysregulation. Early incorporation of genetic sequencing into the diagnostic evaluation, may play a beneficial role in early diagnosis and treatment, particularly in individuals at risk for life-threatening immunodeficiencies and rare disorders. Statement of novelty: We report the diagnostic journey of a patient with compound heterozygous variants in the LRBA gene, along with findings of a NOD2 variant and her known diagnosis of Bartter syndrome. Identifying the variants in LRBA enabled the use of targeted therapies, which have demonstrated clinical and multi-organ benefits in affected individuals.
2024-10-01 | Unraveling the Role of Mitochondrial Dysfunction in the Pathogenesis of Clc-k2-Deficient Bartter Syndrome Mice
Background: Mutations in human ClC-Kb (Clc-k2 in mice) lead to Bartter syndrome (BS) type 3, a congenital renal tubulopathy. Our previous research showed the constitutive deletion of Clc-k2 in mouse kidneys hindered the postnatal development of thick ascending limbs (TALs) through mechanisms not yet fully understood. Our recent extracellular flux analysis revealed that low transport activity in renal tubules resulted in low mitochondrial mass and respiratory capacity. This alarming discovery prompted us to delve deeper into the mitochondrial functions in Clc-k2-deficient TALs and explore the potential of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), the master activator of mitochondrial biogenesis, in rescuing Bartter syndrome. Methods: We analyzed the mitochondrial biogenesis and bioenergetics in isolated TALs using mitochondrial DNA copy numbers, seahorse-based mitochondrial assays, and electron microscopy. We also conducted a comparative transcriptome analysis using isolated Clc-k2 KO vs. wild-type TALs. Uromodulin-positive TAL/DCT cells were pulled down and used for cell cycle and proliferation assays. Pseudohypoaldosteronism type 2 (PHA2) WNK4D561A/+ mutant knockin mice and PGC1-α transgenic mice were crossed with Clc-k2 KO mice to rescue the transport activity/mitochondrial function, respectively. Mouse phenotypes then analyzed and compared. Results: Clc-k2-deficient TALs had reduced mitochondrial-to-nuclear DNA ratio and mitochondrial respiratory capacities, indicating downregulated mitochondrial biogenesis and bioenergetics. Transcriptome analysis confirmed suppression of mitochondrial genes in Clc-k2-deficient TALs. These cells were prone to G1-S cell cycle transition and proliferation delay. PHA2 WNK4D561A/+ mutant improved the mitochondrial mass/function, cell cycle, and proliferation of Clc-k2-deficient TAL cells and rescued the activity of NKCC2 and NCC cotransporter of Clc-k2-deficient mice. Overexpression of PGC1-α in Clc-k2 KO mice improved mitochondrial function of TAL, NKCC2/NCC activities, and BS phenotype. Conclusion: Our results support that low transport activity suppresses mitochondrial biogenesis/bioenergetics in renal tubules, thereby aggravating renal salt wasting, cell cycle delay, and TAL hypoplasia in Clc-k2-deficient BS mice. Mitochondrial-targeting therapy could be promising to BS. Funding: Other NIH Support - R01
2024-08-31 | Regulation of ClC-K/barttin by endocytosis influences distal convoluted tubule hyperplasia.
ClC-K/barttin channels are involved in the transepithelial transport of chloride in the kidney and inner ear. Their physiological role is crucial in humans because mutations in CLCNKB or BSND, encoding ClC-Kb and barttin, cause Bartter's syndrome types III and IV, respectively. In vitro experiments have shown that an amino acid change in a proline-tyrosine motif in the C-terminus of barttin stimulates ClC-K currents. The molecular mechanism of this enhancement and whether this potentiation has any in vivo relevance remains unknown. We performed electrophysiological and biochemical experiments in Xenopus oocytes and kidney cells co-expressing ClC-K and barttin constructs. We demonstrated that barttin possesses a YxxØ motif and, when mutated, increases ClC-K plasma membrane stability, resulting in larger currents. To address the impact of mutating this motif in kidney physiology, we generated a knock-in mouse. Comparing wild-type (WT) and knock-in mice under a standard diet, we could not observe any difference in ClC-K and barttin protein levels or localization, either in urinary or plasma parameters. However, under a high-sodium low-potassium diet, known to induce hyperplasia of distal convoluted tubules, knock-in mice exhibit reduced hyperplasia compared to WT mice. In summary, our in vitro and in vivo studies demonstrate that the previously identified PY motif is indeed an endocytic YxxØ motif in which mutations cause a gain of function of the channel. KEY POINTS: It is revealed by mutagenesis and functional experiments that a previously identified proline-tyrosine motif regulating ClC-K plasma membrane levels is indeed an endocytic YxxØ motif. Biochemical characterization of mutants in the YxxØ motif in Xenopus oocytes and human embryonic kidney cells indicates that mutants showed increased plasma membrane levels as a result of an increased stability, resulting in higher function of ClC-K channels. Mutation of this motif does not affect barttin protein expression and subcellular localization in vivo. Knock-in mice with a mutation in this motif, under conditions of a high-sodium low-potassium diet, exhibit less hyperplasia in the distal convoluted tubule than wild-type animals, indicating a gain of function of the channel in vivo.
2019-08-13 | A novel CLCNKB mutation in a Chinese girl with classic Bartter syndrome: a case report
Bartter syndrome (BS) is a rare autosomal recessive disorder of salt reabsorption at the thick ascending limb of the Henle loop, characterized by hypokalemia, salt loss, metabolic alkalosis, hyperreninemic hyperaldosteronism with normal blood pressure. BS type III, often known as classic BS (CBS), is caused by loss-of-function mutations in CLCNKB (chloride voltage-gated channel Kb) encoding basolateral ClC-Kb. We reported a 15-year-old CBS patient with a compound heterozygous mutation of CLCNKB gene. She first presented with vomiting, hypokalemic metabolic alkalosis at the age of 4 months, and was clinically diagnosed as CBS. Indomethacin, spironolactone and oral potassium were started from then. During follow-up, the serum electrolyte levels were generally normal, but the patient showed failure to thrive and growth hormone (GH) deficiency was diagnosed. The recombinant human GH therapy was performed, and the growth velocity was improved. When she was 14, severe proteinuria and chronic kidney disease (CKD) were developed. Renal biopsy showed focal segmental glomerulosclerosis (FSGS) with juxtaglomerular apparatus cell hyperplasia, and genetic testing revealed a point deletion of c.1696delG (p. Glu566fs) and a fragment deletion of exon 2–3 deletions in CLCNKB gene. Apart from the CBS, ostium secundum atrial septal defect (ASD) was diagnosed by echocardiography. This is the first report of this compound heterozygous of CLCNKB gene in BS Children. Our findings contribute to a growing list of CLCNKB mutations associated with CBS. Some recessive mutations can induce CBS in combination with other mutations.
gene therapies
2026-01-01 | Epigenetic Reprogramming of Renal Pendrin Expression via CRISPR-dCas9-
Bartter Syndrome Type III, consequent to biallelic loss-of-function mutations in CLCNKB, remains incurable despite six decades of palliative pharmacotherapy. The syndrome is characterized by profound metabolic alkalosis (arterial pH 7.51–7.58), hypochloremia (serum Cl⁻ 82– 88 mEq/L), and hypokalemia, arising from impaired chloride reabsorption in the thick ascending limb. Current regimens—non-selective cyclooxygenase inhibition, potassium-sparing diuretics, and electrolyte supplementation—fail to restore physiological acid-base equilibrium, are complicated by nephrotoxicity and growth failure, and do not address the fundamental molecular lesion. Pendrin (SLC26A4), an apical Cl⁻/HCO₃⁻ exchanger expressed in renal β-intercalated cells, constitutes an endogenous bicarbonate secretory pathway that remains epigenetically silenced in Bartter syndrome despite persistent hypochloremic stimuli.
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