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Background Gitelman syndrome (GS) is a rare autosomal recessive renal tubular disorder characterized by hypokalemia, metabolic alkalosis, and hypomagnesemia.While gastrointestinal polyps are common in children, their co-occurrence with GS is exceedingly rare. This report presents the first documented pediatric case in China of GS associated with ileocecal polyps. Case presentation A 5-year-old male presented with paroxysmal periumbilical abdominal pain and persistent hypokalemia (2.72 mmol/L). Imaging revealed a 4 cm × 3 cm × 3 cm ileocecal mass, initially suspected as lymphoma. Colonoscopy identified a pedunculated polyp, excised via electrocoagulation. Histopathology confirmed a juvenile polyp. Genetic testing identified compound heterozygous mutations in the SLC12A3 gene (paternally inherited c.923dup and maternally inherited c.2521 + 253 C > T),confirming GS. Postoperative potassium supplementation stabilized serum potassium (3.27 mmol/L at discharge). Conclusion This report underscores the importance of genetic testing in cases with complex presentations, such as the rare association described here, and raises awareness of potential gastrointestinal comorbidities in GS. Further research is needed to explore shared pathophysiological mechanisms between renal tubular disorders and intestinal polyps.

Background This study aimed to analyze genotype–phenotype correlations in children with Gitelman syndrome (GS). Methods This multicenter retrospective study included 50 Korean children diagnosed with SLC12A3 variants in one or both alleles and the typical laboratory findings of GS. Genetic testing was performed using the Sanger sequencing except for one patient. Results The median age at the diagnosis was 10.5 years (interquartile range, 6.8;14.1), and 41 patients were followed up for a median duration of 5.4 years (interquartile range, 4.1;9.6). A total of 30 different SLC12A3 variants were identified. Of the patients, 34 (68%) had biallelic variants, and 16 (32%) had monoallelic variants on examination. Among the patients with biallelic variants, those ( n  = 12) with the truncating variants in one or both alleles had lower serum chloride levels (92.2 ± 3.2 vs. 96.5 ± 3.8 mMol/L, P  = 0.002) at onset, as well as lower serum potassium levels (3.0 ± 0.4 vs. 3.4 ± 0.3 mMol/L, P  = 0.016), and lower serum chloride levels (96.1 ± 1.9 vs. 98.3 ± 3.0 mMol/L, P  = 0.049) during follow-up than those without truncating variants ( n  = 22). Patients with monoallelic variants on examination showed similar phenotypes and treatment responsiveness to those with biallelic variants. Conclusions Patients with GS who had truncating variants in one or both alleles had more severe electrolyte abnormalities than those without truncating variants. Patients with GS who had monoallelic SLC12A3 variants on examination had almost the same phenotypes, response to treatment, and long-term prognosis as those with biallelic variants.

Background Gitelman syndrome (GS) is an inherited renal tubular disorder characterized by hypokalemic alkalosis and hypomagnesemia, due to biallelic pathogenic variants in the solute carrier family 12 member 3 ( SLC12A3 ) gene encoding a sodium-chloride (Na-Cl) cotransporter (NCC). This work aimed at identifying SLC12A3 variants in the GS pedigree and reveal the effect of the mutations on protein structure and function. Methods Whole-exome sequencing (WES) and Sanger sequencing were performed in the pedigree. Configuration prediction of two mutant NCC proteins were achieved using SWISS-MODEL. The SLC12A3 missense mutants were generated by site-specific mutagenesis, and the protein expression, location and Na + uptake activity were assessed by using the HEK293T cell line. Results Genetic analysis identified novel compound heterozygous SLC12A3 variants (c.718G > A/p.E240K and c.2675T > C/p.L892P) in the patient with typical GS phenotype. Both of her parents, elder brother and her son carried the heterozygous p.L892P variant, but only the elder brother exhibited mild hypokalemia. Bioinformatics tools predicted that both mutations were highly species conserved and pathogenic. The prediction of mutant protein indicated that p.E240K and p.L892P altered protein’s secondary and three-dimensional (3D) structure and stability. Functional experiments revealed decreased protein expression and Na + uptake activity caused by these two variants, especially the p.L892P variant. Conclusion Our study presents the genetic and functional evidence for the novel compound heterozygous loss-of-function variants in SLC12A3 that may synergistically cuase GS, and expands the mutation spectrum of SLC12A3 variants in patients with GS.

Background Gitelman syndrome (GS) is a rare tubulopathy with clinical and genetic heterogeneity. This study aimed to investigate the characteristics of Chinese GS patients. Methods The diagnosis of GS was established by combining clinical phenotypes with genetic testing, after which the clinical, biochemical, and genetic data were statistically analyzed. Results We reported 95 Chinese GS patients aged 2–52 years. The younger group (≤ 16 years) had more frequent febrile episodes (20.4% vs. 4.3%, P  = 0.028) and nausea/vomiting (12.2% vs. 0.0%, P  = 0.027) but fewer paresthesia/numbness (20.4% vs. 43.5%, P  = 0.026) and palpitations (8.2% vs. 37.0%, P  = 0.001), along with higher serum potassium and magnesium levels (2.86 ± 0.45 mmol/L vs. 2.67 ± 0.38 mmol/L, P  = 0.034; 0.65 ± 0.14 mmol/L vs. 0.58 ± 0.16 mmol/L, P  = 0.031) than the older group (> 16 years). Moreover, serum potassium and magnesium levels were positively correlated and both were negatively correlated with age. Additionally, Among 170 detected SLC12A3 variants, 73 distinct variants were identified, including six novel ones. The compound heterozygous group exhibited higher serum magnesium levels compared to the heterozygous and homozygous groups (0.65 ± 0.17 mmol/L vs. 0.56 ± 0.09 mmol/L, P  = 0.015; 0.65 ± 0.17 mmol/L vs. 0.51 ± 0.07 mmol/L, P  < 0.001). Age at diagnosis was associated with variant types. Conclusion The study characterized the phenotypic and genotypic features of Chinese GS patients, highlighting age and mutation genotype as key factors influencing phenotype, underscoring the importance of standardized potassium and magnesium supplementation, and expanding the known mutation spectrum with novel variants.

As the most frequent inherited tubulopathy, Gitelman syndrome (GS), has an incidence that has increased worldwide. The distribution of gene mutation hotspots deserves exploration. In addition, GS is not a benign syndrome; however, the diagnostic process of GS has not yet been completely detailed. We report two cases of GS pedigrees involving two previously unreported mutations, c. 676G>A, p. A226T and c. 421G>A, p. G141R, in the gene and reviewed relevant literature. We searched the literature for nucleotide of in PubMed and other databases as of April 20, 2020. A total of 1,794 detected mutated alleles in 939 patients worldwide were included in this study. Splicing mutations and p. Gly741Arg were mutation hotspots in a European population. P. Leu858His and p. Thr60Met were mutation hotspots in an Asian population. P. Leu858His and p. Thr180Lys were considered mutation hotspots in the Japanese population, while p. Thr60Met and p. Asp486Asn were considered mutation hotspots in the Chinese population. Our results identified two novel mutation sites (c. 676G>A, p. A226T and c. 421G>A, p. G141R), if their pathogenicity was determined this could contribute to the enrichment of database resources on GS. Our study has compiled the most comprehensive gene mutation database in the world thus far to reveal that different regions have different mutation hotspots in SLC12A3. Moreover, the establishment of a diagnostic process for GS has important implications for confirmed cases.

We report a Gitelman syndrome (GS) pedigree from a Chinese family. The proband, a middle-aged man, presented with hypokalemia, hypomagnesemia, and unilateral limb paralysis. After a comprehensive evaluation, peripheral neuropathy and the cranial or spinal cord disorders were ruled out. Genetic testing identified a homozygous c.1964G > A variant in the SLC12A3 gene. Despite potassium and magnesium supplementation, the patient’s clinical symptoms persisted. Additionally, 13 heterozygous family members, including his parents, showed no typical GS manifestations. However, the proband’s two brothers, who also carried the same homozygous mutation and exhibited hypokalemia and hypomagnesemia, did not develop unilateral limb paralysis. This case suggests that the c.1964G > A variant may be associated with a severe GS phenotype, including unilateral limb paralysis. Clinicians should be aware of the diagnostic challenges and therapeutic limitations in managing GS, particularly in patients with severe manifestations. Genetic testing is essential for accurate diagnosis, and ongoing monitoring and symptomatic management are critical to improving the quality of life for affected individuals.

Purpose Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. Methods We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8 + T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. Results Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. Conclusion Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

Background Gitelman syndrome (GS) is a type of salt‐losing tubular disease, most of which is caused by SLC12A3 gene variants, and missense variants account for the majority. Recently, the phenomenon of exon skipping, in which variants disrupt normal pre‐mRNA splicing, has been related to a variety of diseases. Therefore, we hypothesize that a certain proportion of SLC12A3 variants can result in disease via interfering with the normal splicing process. Methods We analyzed 342 previously presumed SLC12A3 missense variants using bioinformatics programs and identified candidate variants that may alter the splicing of pre‐mRNA through minigene assays. Results Our study revealed that, among ten candidate variants, six variants (c.602G>A, c.602G>T, c.1667C>T, c.1925G>A, c.2548G>C, and c.2549G>C) led to complete or incomplete exon skipping by affecting exonic splicing regulatory elements and/or disturbing canonical splice sites. Conclusion It is worth mentioning that this is the largest study on pre‐mRNA splicing of SLC12A3 exonic variants. In addition, our study emphasizes the importance of detecting splicing function at the mRNA level in GS and indicates that minigene analysis is a valuable tool for splicing functional assays of variants in vitro. The purpose of this study was to identify the effect of previously presumed missense SLC12A3 variants on pre‐mRNA splicing using bioinformatics tools and minigenes. The results revealed that, among ten candidate variants, six variants (c.602G>A, c.602G>T, c.1667C>T, c.1925G>A, c.2548G>C, and c.2549G>C) led to complete or incomplete exon skipping by affecting exonic splicing regulatory elements and/or disturbing canonical splice sites. It is worth mentioning that this is the largest study on pre‐mRNA splicing of SLC12A3 exonic variants, and our study emphasizes the importance of detecting splicing function at the mRNA level in GS and indicates that minigene analysis is a valuable tool for splicing functional assays of variants in vitro.

A 14-year-old male patient who suffered from limb numbness, fatigue, and hypokalemia was considered Graves’ disease (GD) complicated with thyrotoxic periodic paralysis (TPP) at the first diagnosis. Although with the treatment of antithyroid drugs, he developed severe hypokalemia and rhabdomyolysis (RM). Further laboratory tests revealed hypomagnesemia, hypocalciuria, metabolic alkalosis, hyperrenin, and hyperaldosteronemia. Genetic testing revealed compound heterozygous mutations in the SLC12A3 gene (c.506-1G > A, c.1456G > A) encoding the thiazide-sensitive sodium-chloride cotransporter, which presented a definitive diagnosis of Gitelman syndrome (GS). Moreover, gene analysis revealed his mother diagnosed with subclinical hypothyroidism due to Hashimoto’s thyroiditis carried the c.506-1G > A heterozygous mutation in the SLC12A3 gene and his father carried the c.1456G > A heterozygous mutation in the SLC12A3 gene. His younger sister who had hypokalemia and hypomagnesemia carried the same compound heterozygous mutations as the proband and was diagnosed with GS as well, but with a much milder clinical presentation and better treatment outcome. This case suggested the potential relationship between GS and GD, clinicians should strengthen the differential diagnosis to avoid missed diagnosis.

Background Gitelman syndrome (GS) is an autosomal recessive disorder and mild variant of classic Bartter syndrome. The latter is caused by defects in the genes CLCNKB and/or CLCNKA (chloride voltage-gated channel Ka and Kb). Patients with GS usually have loss-of-function mutations in SLC12A3 . No patient has been reported with compound heterozygous mutations in these genes. We report a girl with GS with a paternally inherited heterozygous mutation in SLC12A3 , and maternally inherited heterozygous variants in both CLCNKB and CLCNKA . Case presentation In this report, we reported a female patient (8 y and 10 mo) who had growth retardation (111.8 cm, − 1.62 standard deviation height for age) and normal blood pressure, with persistent hypokalemia, hypomagnesemia, hypocalciuria, hypochloremic alkalosis, and elevated levels of plasma renin and aldosterone. Her younger brother, father, and paternal grandmother all had histories of mild low levels of plasma potassium (3.0–3.5 mmol/L), which were rectified by potassium-rich foods. The genomic DNA of the patient, younger brother, parents, and grandparents were screened for gene variations and pedigree analysis using trio whole exome sequencing (WES). The candidate variants were validated by Sanger sequencing. Protein-protein interaction analysis utilized the following databases: Biogrid, MINT, HPRD, STRING, IntAct, iRefIndex, and ppiTrim. The trio WES screening showed that the patient has paternally inherited SLC12A3 p.N359K, and maternally inherited CLCNKB p.L94I. The paternal grandmother and younger brother are both carriers of SLC12A3 p.N359K. According to the STRING database, SLC12A3 and CLCNKB proteins may interact or coexpress with proteins associated with GS. Conclusions Based on clinical phenotypes, genetic evidence of the pedigree, and previous reported studies, this case of GS indicates a digenetic inheritance of SLC12A3 and CLCNKB that resulted in renal tubular dysfunction perhaps, due to a genetic double-hit mechanism. The putative pathogenicity of the CLCNKB p.L94I variant requires confirmation.