Paving the way for Bartter syndrome type 3 drug discovery: a hope from basic research

Imbrici, Paola; Conte, Diana; Liantonio, Antonella

doi:10.1113/jp274645

Cited by 4 publications

(5 citation statements)

References 6 publications

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“…This conclusion has also been achieved by other authors [12]. In addition, based on genetic abnormality a speci c therapy for each defect can be develop in next future [13]. As one knows, population differences have been observed among patients with the same clinical diagnosis [21].…”

Section: Discussionsupporting

confidence: 57%

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Genetic spectrum of Brazilian suspected Bartter Syndrome Patients

Achl¹,

JCdOA²,

Fonseca³

et al. 2020

Preprint

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Background This paper’s goal is to show the genetic study results of suspected Bartter syndrome (BS) patients followed in a pediatric nephrology reference center in Sao Paulo/Brazil, verify a possible genotype-phenotype correlation and compare the genetic results with those from other regions of the globe. Results This descriptive study included 22 patients (21 families) with clinical diagnosis of BS. Pathogenic variants in BS-related genes were detected in 19/22 patients. No BS-related genes were detected in three patients (one case of Congenital Chloride Diarrhea and two siblings with clinical Antenal BS that, in fact, had Gitelman Syndrome). We observed that 16/19 BS-confirmed patients had CLCNKB mutations (BS type 3) with a large phenotypical diversity. Among them, the deletion of the entire gene (del 1–20) was the most frequent variant detected. Interestingly, we observed that patients with homozygous or heterozygous del 1–20 presented earlier manifestations than patients with other CLCNKB mutations. They presented no other clinical significant difference. Conclusion This study demonstrates the importance of an appropriate investigation of clinically suspected BS patients to rule out pseudo-BS. This data also confirms the difficult to differentiate these patients based just on clinical findings, similar to what has been reported in other studies. There were patients with clinical Antenatal BS in whom the genetic analysis confirmed the final diagnosis of GS or BS type 3. Among BS cases, BS type 3 was the most frequent in this Brazilian cohort and del 1–20 was the most frequently variant detected. In addition, BS type 3 patients with homozygous or heterozygous del 1–20 had earlier manifestations than patients with other CLCNKB mutations. Brazilian community has a particular characteristic miscegenation as well as different origins such as Europeans, Africans and Asians and comparing our results with those from other regions we can suppose the genetic background of this Brazilian cohort is related to African and Portuguese inheritance, probably originated in the early period of immigration (colonization and slavery period). Limitations: low number of patients from a single center. However, as a rare disease all data can contribute to the improvement for diagnosis and treatment.

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Section: Discussionsupporting

confidence: 57%

“…This group has been classi ed based on genetic ndings [12]. Therefore, the genetic study in this group of patients is necessary to clarify the true pathway of the disease, and serves as a base to implement speci c treatments [13]. In this approach, it is very important to be alert for population differences.…”

Section: Subtypes Of Bsmentioning

confidence: 99%

Genetic spectrum of Brazilian suspected Bartter Syndrome Patients

Achl¹,

JCdOA²,

Fonseca³

et al. 2020

Preprint

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“…These evidences add support to the idea that the recovery, even partial, of ClC-Kb impaired function could be a correct therapeutic strategy to treat BS. Such an approach could offer a unique opportunity to the pharmacotherapy of BS, switching from a symptomatic therapy to a personalized defect-targeted cure, using molecules targeting the specific channel defect induced by a mutation (Terragni et al, 2017;Imbrici et al, 2017b).…”

Section: Perspectives For Bs Therapymentioning

confidence: 99%

“…As such, BS affected patients are treated with cyclooxygenase inhibitors such as indomethacin to reduce elevated PGE2 levels, potassium and magnesium supplements, and potassium-sparing diuretics to normalize electrolyte balance, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers to counteract high angiotensin II plasma levels and proteinuria (Alhammadi et al, 2014;Zieg et al, 2016;Yang et al, 2018;Kleta and Bockenhauer, 2018). The possibility to target BS mutations with specific molecular defect with ClC-K channels modulators would be appealing in the perspective to ensure a specific and safer therapy to BS patients (Imbrici et al, 2017b). In this context, drug repositioning could be a pursuable pharmacological strategy (Loizzi et al, 2013;Imbrici et al, 2018;Perucca and Perucca, 2019).…”

Section: Introductionmentioning

confidence: 99%

Functional Study of Novel Bartter’s Syndrome Mutations in ClC-Kb and Rescue by the Accessory Subunit Barttin Toward Personalized Medicine

et al. 2020

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Type III and IV Bartter syndromes (BS) are rare kidney tubulopathies caused by loss-offunction mutations in the CLCNKB and BSND genes coding respectively for the ClC-Kb chloride channels and accessory subunit barttin. ClC-K channels are expressed in the Henle's loop, distal convoluted tubule, and cortical collecting ducts of the kidney and contribute to chloride absorption and urine concentration. In our Italian cohort, we identified two new mutations in CLCNKB, G167V and G289R, in children affected by BS and previously reported genetic variants, A242E, a chimeric gene and the deletion of the whole CLCNKB. All the patients had hypokalemia and metabolic alkalosis, increased serum renin and aldosterone levels and were treated with a symptomatic therapy. In order to define the molecular mechanisms responsible for BS, we co-expressed ClC-Kb wild type and channels with point mutations with barttin in HEK 293 cells and characterized chloride currents through the patch-clamp technique. In addition, we attempted to revert the functional defect caused by BS mutations through barttin overexpression. G167V and A242E channels showed a drastic current reduction compared to wild type, likely suggesting compromised expression of mutant channels at the plasma membrane. Conversely, G289R channel was similar to wild type raising the doubt that an additional mutation in another gene or other mechanisms could account for the clinical phenotype. Interestingly, increasing ClC-K/barttin ratio augmented G167V and A242E mutants' chloride current amplitudes towards wild type levels. These results confirm a genotype-phenotype correlation in BS and represent a preliminary proof of concept that molecules functioning as molecular chaperones can restore channel function in expression-defective ClC-Kb mutants.

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“…Furthermore, the patient would always be prone to severe metabolic and electrolyte imbalance during common and even mild pediatric illness. Therefore, there is a need for novel treatments and genetic testing of these patients is essential to serve as a basis for implementing specific target therapies in the near future [13].…”

Section: Introductionmentioning

confidence: 99%

Bartter Syndrome-Related Variants Distribution: Brazilian Data and Its Comparison with Worldwide Cohorts

Vaisbich

Messa

Rangel-Santos

et al. 2023

Nephron

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Background: Genetic testing is recommended for accurate diagnosis of Bartter syndrome (BS) and serves as a basis for implementing specific target therapies. However, populations other than Europeans and North Americans are underrepresented in most databases and there are uncertainties in the genotype-phenotype correlation. We studied Brazilian BS patients, an admixed population with diverse ancestry. Methods: We evaluated the clinical and mutational profile of this cohort and performed a systematic review of BS mutations from worldwide cohorts. Results: Twenty-two patients were included; Gitelman syndrome was diagnosed in 2 siblings with antenatal BS and congenital chloride diarrhea in 1 girl. BS was confirmed in 19 patients: BS type 1 in 1 boy (antenatal BS); BS type 4a in 1 girl and BS type 4b in 1 girl, both of them with antenatal BS and neurosensorial deafness; BS type 3 (CLCNKB mutations): 16 cases. The deletion of the entire CLCNKB (1–20 del) was the most frequent variant. Patients carrying the 1–20 del presented earlier manifestations than those with other CLCNKB-mutations and the presence of homozygous 1–20 del was correlated with progressive chronic kidney disease. The prevalence of the 1–20 del in this BS Brazilian cohort was similar to that of Chinese cohorts and individuals of African and Middle Eastern descent from other cohorts. Conclusion: This study expands the genetic spectrum of BS patients with different ethnics, reveals some genotype/phenotype correlations, compares the findings with other cohorts, and provides a systematic review of the literature on the distribution of BS-related variants worldwide.

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Paving the way for Bartter syndrome type 3 drug discovery: a hope from basic research

Cited by 4 publications

References 6 publications

Genetic spectrum of Brazilian suspected Bartter Syndrome Patients

Genetic spectrum of Brazilian suspected Bartter Syndrome Patients

Functional Study of Novel Bartter’s Syndrome Mutations in ClC-Kb and Rescue by the Accessory Subunit Barttin Toward Personalized Medicine

Bartter Syndrome-Related Variants Distribution: Brazilian Data and Its Comparison with Worldwide Cohorts

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