A missense variant in SLC12A3 gene enhances aberrant splicing causing Gitelman syndrome.

Gitelman syndrome (GS) is the most prevalent genetic tubulopathy characterized by several electrolyte abnormalities, including hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, and hyperreninemic hyperaldosteronism. These features are caused by a bi-allelic mutation in the SLC12A3 gene. In this report, we present a case of GS in an asymptomatic woman who incidentally exhibited hypokalemia during an antenatal check-up. Her biochemical profile was consistent with GS. Genetic analysis revealed two heterozygous variants in trans, namely, NM_001126108.2:c.625C>T; p.(Arg209Trp) and c.965C>T; p.(Ala322Val). The c.625C>T; p.(Arg209Trp) variant has previously been experimentally confirmed as a loss-of-function (LOF) variant. However, the functional impact of the c.965C>T variant, located at the 5 prime end of exon 8, has not been fully elucidated. Through the utilization of both complementary DNA (cDNA) and minigene analysis, we confirmed that the c.965C>T variant can generate two distinct cDNA transcripts. The first transcript carries a missense mutation, p.(Ala322Val) in the full SLC12A3 transcript, while the second transcript consists of an in-frame deletion of both exons 7 and 8 in the SLC12A3 transcript, in which may result in the loss of transmembrane regions 5 - 6 involved in chloride transport. Our findings provide insights into the intricate mechanisms of splicing, highlighting how a variant in one exon can remotely influence the transcription of an upstream exon, as observed with the variant in exon 8 impacting the transcription of exon 7.

Hypokalemia Induced Partial Nephrogenic Diabetes Insipidus: A Case Report.

ABSTRACT: Diabetes insipidus is a condition characterised by a large volume of diluted urine production and increased thirst. In this case report, a 49-year-old gentleman presented with 3 months of polyuria and polydipsia. He had a repeated history of hypokalemia. On the evaluation of polyuria and polydipsia, he was diagnosed with partial nephrogenic diabetes insipidus based on his inability to concentrate urine after a water deprivation test and his less than 50% response to exogenous desmopressin. On the evaluation of recurrent hypokalemia, the investigation reports met biochemical criteria for the diagnosis of Gitelman syndrome. He was encouraged to increase his fluid intake as required, and potassium chloride supplementation relieved his symptoms. This case report demonstrates the reversibility of nephrogenic diabetes insipidus with a correction of hypokalemia.

Clinical Features and Unusual Heterozygous Mutations in Patients with Renal Hypokalemia.

BACKGROUND: Renal hypokalemia is associated with mutation. This study aimed to investigate the clinical features and pathogenic mutations in patients with renal hypokalemia. METHODS: The patients with hypokalemia were enrolled, and the renal function, thyroid function, renin-aldosterone system, urinary potassium excretion, and exome sequencing were performed. The correlation between the clinical phenotypes and causative genes was assessed. RESULTS: Five patients with hypokalemia were enrolled and diagnosed as tubular hypokalemia. The patients with common clinical manifestations were difficult to differentiate based on atypical laboratory findings. The results of the genetic analysis were as follows: both patient 1 and patient 2 were heterozygous for the c.C625T mutation of the KCNJ1 gene, which is responsible for Bartter syndrome. Patient 3 was heterozygous for the c.G298A mutation of the ATP6V1B1 gene, which is responsible for renal tubular acidosis. Patient 4 had a compound heterozygous mutation of c.G893A of the BSND gene, responsible for Bartter syndrome, and c.1029+5G>A, the ATP6V0A4 gene responsible for distal renal tubular acidosis. Patient 5 had Gitelman syndrome and carried the compound heterozygous mutations c.C1963T and c.G2029A of the SLC12A3 gene. All the above loci were known heterozygous mutations. CONCLUSIONS: The unusual heterozygous mutations were identified in five renal hypokalemia patients. Molecular diagnosis of tubular hypokalemia was conducive to accurate diagnosis and treatment.

Untangling the Uncertain Role of Overactivation of the Renin-Angiotensin-Aldosterone System with the Aging Process Based on Sodium Wasting Human Models.

Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.

Gitelman syndrome with primary hyperparathyroidism: A case report.

BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessive inherited salt-losing tubulopathy, typically devoid of hypercalcemia. Herein, we described one patient of GS presenting with hypercalcemia concomitant with primary hyperparathyroidism (PHPT). METHODS: On September 28, 2020, a middle-aged female patient was admitted to our hospital with a 12-year history of hypokalemia and hypomagnesemia. Laboratory examinations unveiled hypokalemia with renal potassium wasting, hypomagnesemia, metabolic alkalosis, hypocalciuria, and gene sequencing revealed a homozygous mutation in SLC12A3 (c.179C > T [p.T60M]). Subsequently, the diagnosis of GS was confirmed. In addition, the patient exhibited hypercalcemia and elevated levels of parathyroid hormone. Parathyroid ultrasound revealed left parathyroid hyperplasia, consistent with PHPT. Following aggressive treatment with potassium chloride and magnesium oxide, her serum potassium rose to 3.23 mmol/L, serum magnesium was 0.29 mmol/L, and her joint pain was relieved. RESULTS: Based on the patient's medical history, laboratory findings, and gene sequencing results, the definitive diagnosis was GS concomitant with PHPT. CONCLUSION: PHPT should be taken into consideration when patients diagnosed with GS exhibit hypercalcemia. While the serum potassium level readily exceeded the target threshold, correcting hypomagnesemia proved challenging, primarily because PHPT augments urinary magnesium excretion.

Concurrent Gitelman Syndrome and Hyperthyroidism: Diagnostic Challenges in a 51-Year-Old Patient.

BACKGROUND Gitelman syndrome (GS) is an uncommon autosomal recessive inherited disease caused by inactivating mutations in the SLC12A3 gene located on chromosome 16q13, resulting in distal tubular dysfunction. Most cases are detected during routine examinations in adulthood, due to hypokalemia and alkalosis. GS needs to be distinguished from diseases that cause hypokalemia, such as Classic Bartter syndrome and hyperthyroidism. In individual cases, GS and hyperthyroidism occur simultaneously, which is prone to misdiagnosis. CASE REPORT A 51-year-old woman with intermittent palpitations and lower limb fatigue for 4 years received a diagnosis of hypokalemia at a local hospital. Treatment with potassium supplementation did not improve the patient's palpitations and fatigue. After coming to our hospital for examination, it was found that the patient had hyperthyroidism. After receiving treatment of hyperthyroidism remission and sufficient potassium replacement, the patient's serum potassium level remained low. Meanwhile, the patient had hypomagnesemia and metabolic alkalosis. Subsequently, according to our suggestion, the patient continued to take oral supplements of potassium and magnesium, while also started on spironolactone. We convinced the patient to undergo genetic testing and discovered compound heterozygous mutations in the SLC12A3 gene, which presented a definitive diagnosis of GS. In the following 3 months, the patient's serum potassium level was within the normal range, and the dose of methimazole was reduced. CONCLUSIONS As a rare disease, GS may have only mild or occasional manifestations, making it prone to misdiagnosis. GS remains therapeutically challenging, and future progress in treatment will depend on further research of the disease.

Pathophysiological role of Na-Cl cotransporter in kidneys, blood pressure, and metabolism.

The Na-Cl cotransporter (NCC) is a well-recognized regulator of ion transportation in the kidneys that facilitates Na+ reabsorption in the distal convoluted tubule. It is also the pharmacologic inhibitory target of thiazide diuretics, a class of front-line antihypertensive agents that have been widely used for decades. NCC is a potent regulator of Na+ reabsorption and homeostasis. Hence, its overactivation and suppression lead to hypertension and hypotension, respectively. Genetic mutations that affect NCC function contribute to several diseases such as Gordon and Gitelman syndromes. We summarized the role of NCC in various physiologic processes and pathological conditions, such as maintaining ion and water homeostasis, controlling blood pressure, and influencing renal physiology and injury. In addition, we discussed the recent advancements in understanding cryo-EM structure of NCC, the regulatory mechanisms and binding mode of thiazides with NCC, and novel physiologic implications of NCC in regulating the cross-talk between the immune system and adipose tissue or the kidneys. This review contributes to a comprehensive understanding of the pivotal role of NCC in maintaining ion homeostasis, regulating blood pressure, and facilitating kidney function and NCC's novel role in immune and metabolic regulation.

Paradoxes in magnesium transport in type 1 Bartter's syndrome and Gitelman's syndrome: a modeling analysis.

Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na+ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg2+) and calcium (Ca2+) transport in the kidney, significant alterations in the transport of these two electrolytes are observed in type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rats to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg2+ and Ca2+ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter patterns, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg2+ preservation but not Ca2+, whereas in Gitelman's syndrome, those adaptations favor Ca2+ preservation over Mg2+. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.NEW & NOTEWORTHY Although changes in Ca2+ excretion in type 1 Bartter's syndrome and Gitelman's syndrome are well understood, Mg2+ excretion displays an interesting paradox. This computational modeling study provides insights into how renal adaptations in these two disorders impact Ca2+ and Mg2+ transport along different nephron segments. Model simulations showed that nephron adaptations favor Mg2+ preservation over Ca2+ in Bartter's syndrome and Ca2+ preservation over Mg2+ in Gitelman's syndrome and are stronger in females than in males.

Clinical and genetic analysis of a case of Gitelman syndrome accompanied with Graves disease and adrenocortical adenoma: A case report.

RATIONALE: Gitelman syndrome (GS), also known as familial hypokalemia and hypomagnesemia, is a rare autosomal recessive inherited disease caused by primary renal desalinization caused by impaired reabsorption of sodium and chloride ions in the distal renal tubules. We report a case of clinical and genetic characteristics of GS accompanied with Graves disease and adrenocorticotrophic hormone (ACTH)-independent adrenocortical adenoma. PATIENT CONCERNS: The patient is a 45 year old female, was admitted to our hospital, due to a left adrenal gland occupying lesion as the chief complaint. DIAGNOSIS: The patient was finally diagnosed as GS with Graves disease and adrenocortical adenoma. INTERVENTIONS: Potassium magnesium aspartate (1788 mg/d, taken orally 3 times a day (supplement a few times a day, intake method, treatment duration). Contains 217.2 mg of potassium and 70.8 mg of magnesium, and potassium chloride (4.5 g/d, taken orally 3 times a day (supplement a few times a day, intake method, and treatment duration); Potassium 2356 mg), spironolactone (20 mg/d, taken orally once a day (supplement a few times a day, intake method, treatment duration). After 3 months of treatment, the patient's blood potassium fluctuated between 3.3-3.6 mmol/L, and blood magnesium fluctuated between 0.5-0.7 mmol/L, indicating a relief of fatigue symptoms. OUTCOMES: On the day 6 of hospitalization, the symptoms of dizziness, limb fatigue, fatigue and pain were completely relieved on patient. In the follow-up of the following year, no recurrence of the condition was found. LESSONS: The novel c.1444-10(IVS11)G > A variation may be a splicing mutation. The compound heterozygous mutations of the SLC12A3 gene may be the pathogenic cause of this GS pedigree.

Genotype-phenotype correlations in children with Gitelman syndrome.

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.

Adult classic Bartter syndrome: a case report with 5-year follow-up and literature review.

Bartter syndrome (BS) is a rare, inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism, hypokalemia, hypochloremia, metabolic alkalosis, and low-to-normal blood pressure. Classic BS, or BS Type 3, the most common subtype in the Asian population, is caused by a molecular defect in ClC-Kb, a voltage-gated chloride channel in renal tubules, due to CLCNKB gene mutation. Because the onset of BS is more common in children than in adults, the diagnosis, treatment outcomes, genotype/phenotype association, and follow-up of adult-onset BS Type 3 are limited. This case report describes the findings in a 20-year-old man who was admitted with hypokalemic paralysis, with clinical manifestations were similar to those of Gitelman syndrome (GS); however, the patient was later diagnosed to have BS Type 3 through genetic testing (NM_000085.4 (CLCNKB): c.1052G>T). A literature review showed that no homozygous mutations have been reported to date. After 5 years of treatment and follow-up, we found that this genotype requires high levels of potassium and is prone to urinary protein and metabolic syndrome. Distinguishing adult-onset BS from GS is challenging in clinical practice. However, genetic diagnosis can help solve this problem effectively, and genotypes play a guiding role in treatment planning.

[Genetic analysis of two patients with Gitelman syndrome].

OBJECTIVE: To explore the genetic etiology of two patients with Gitelman syndrome (GS). METHODS: Two patients who had presented at the Linyi People's Hospital in January and June 2022 respectively were selected as the study subjects. Peripheral blood samples of them were collected and subjected to whole exome sequencing (WES). Electrolyte levels in their serum and urine were detected. Candidate variants were verified by Sanger sequencing. PyMOL software was used to predict the impact of the variants on the protein structure. RESULTS: Patient 1 was a 27-year-old female with decreased serum levels of sodium, potassium, chloride and magnesium, along with decreased urine chloride and calcium. WES revealed that she has harbored compound heterozygous variants of the SLC12A3 gene, namely c.1456G>A (p.D486N) and c.179C>T (p.T60M). The former was inherited from her mother and known to be pathogenic. Patient 2 was a 4-year-old male with lower serum sodium, chloride and magnesium levels, and his serum potassium level was found to be critically low. He was found to harbor compound heterozygous variants of c.602-16G>A and c.805_806insTTGGCGTGGTCTCGGTCA (p.V268_T269insIGVVSV) of the SLC12A3 gene, which were inherited from his mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+PM2_Supporting+PP3; PVS1+PM2_Supporting+PM4). CONCLUSION: The above heterozygous variants of the SLC12A3 gene probably underlay the GS in these patients.

A case of pseudo-Bartter/Gitelman syndrome caused by long-term laxative abuse, leading to end-stage kidney disease.

Pseudo-Bartter/Gitelman syndrome (PBS/PGS) is a disorder that presents with hypokalemia and metabolic alkalosis resembling Gitelman syndrome (GS) due to secondary factors, such as lifestyle and /or medicines. Notably, PBS/PGS is more likely to cause renal dysfunction than GS. We report the first case of PBS/PGS due to long-term laxative abuse leading to end-stage kidney disease (ESKD). The patient was a 49-year-old woman with a history of constipation since school, who had used excessive doses of laxatives on her own judgment for nine years at least from 22 years of age. Two years later, blood tests revealed hypokalemia (serum K 3.1 mEq/L), and nine years later, the patient's renal function began to deteriorate (Cr-eGFR 48.7 mL/min/1.73 m2). Since abuse of laxatives was suspected as the cause, it was changed to the proper dosage of laxatives. At 33 years, the patient developed acute kidney injury (AKI), due to a urinary tract infection, and required intensive treatment, including hemodialysis. Although the patient was eventually weaned off dialysis, the renal function did not recover to pre-AKI levels. In suspected GS, comprehensive genetic testing for renal disease-related genes was performed; however, no obvious pathogenic variants were identified. Thereafter, despite decreasing the laxative doses and potassium supplementation, her renal function continued to decline. At 49 years, the patient developed ESKD and was started on maintenance hemodialysis. PBS/PGS is a disease that can lead to ESKD. An early diagnosis of PBS/PGS is crucial to prevent renal function deterioration, and the underlying causes should be removed immediately.

A novel homozygous SLC12A3 mutation causing Gitelman syndrome with co-existent autoimmune thyroiditis: a case report and review of the literature.

Gitelman syndrome is a rare, autosomal recessively inherited tubulopathy manifesting with hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Common symptoms include fatigue, myalgia, reduced performance capacity, tetany, paresthesia, and delayed growth. However, as reported in the literature, diagnosis in some patients is prompted by an incidental finding of hypokalemia. GS develops due to mutations in the SLC12A3 gene, which encodes the thiazide-sensitive Na-Cl cotransporter. Many variants in the SLC12A3 gene causing GS have been reported in literature. A new pathogenic homozygous mutation (c.2612G > T), absence of hypomagnesemia, and accompanying autoimmune thyroiditis are remarkable in our patient. There are a few Gitelman syndrome cases that are complicated with autoimmune thyroiditis in the literature. In this study, we present a case of Gitelman syndrome with a novel homozygous mutation and accompanying autoimmune thyroiditis and review of the literature.

Interpreting epigenetic causes of recurrent hypokalemia and seizures: Gitelman syndrome co-exist with pseudohypoparathyroidism type 1B.

We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year history of seizures, tetany, and numbness of the extremities. Further examinations showed recurrent hypokalemia, inappropriate kaliuresis, hypocalcemia, hyperphosphatemia, and elevated PTH levels. A novel variant of autosomal recessive GS (p.Val287Met SLC12A3) and a novel 492.3Kb deletion containing the whole of STX16, were discovered by a whole-exome sequencing. Following the diagnosis, calcitriol, calcium, and potassium supplements were started. Hematuria calcium and phosphorus levels, as well as blood potassium levels, have recovered and remained within normal ranges after 3 years of follow-up. Our findings have important consequences for supporting the idea that heterozygosity for variants have effects on the patients' clinical performance with autosomal recessive inheritance disorders. Further study is need for the putative effects of the variant. Likewise, further investigation with regards to the gene-gene interaction relations between GS and other electrolyte imbalance disorders is warranted.

Long-Term Indomethacin Treatment in a Chinese Child with Gitelman Syndrome: Case Report and Literature Review on its Efficacy and Tolerance.

BACKGROUND Gitelman syndrome (GS) is a rare inherited autosomal recessive salt-losing renal tubulopathy. Early-onset GS is difficult to differentiate from Bartter syndrome (BS). It has been reported in some cases that cyclooxygenase (COX) inhibitors, which pharmacologically reduce prostaglandin E2(PGE2) synthesis, are helpful for GS patients, especially in children, but the long-term therapeutic effect has not yet been revealed. CASE REPORT A 4-year-old boy was first brought to our hospital for the chief concern of short stature and growth retardation. Biochemical tests demonstrated severe hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis. The patient's serum magnesium was normal. He was diagnosed with BS and treated with potassium supplementation and indomethacin and achieved stable serum potassium levels and slow catch-up growth. At 11.8 years of age, the patient showed hypomagnesemia and a genetic test confirmed that he had GS with compound heterozygous mutations in the SLC12A3 gene. At the age of 14.8 years, when indomethacin had been taken for nearly 10 years, the boy reported having chronic stomachache, while his renal function remained normal. After proton pump inhibitor and acid inhibitor therapy, the patient's symptoms were ameliorated, and he continued to take a low dose of indomethacin (37.5 mg/d divided tid) with good tolerance. CONCLUSIONS Early-onset GS in childhood can be initially misdiagnosed as BS, and gene detection can confirm the final diagnosis. COX inhibitors, such as indomethacin, might be tolerated by pediatric patients, and long-term therapy can improve the hypokalemia and growth retardation without significant adverse effects.

Gitelman syndrome combined with diabetes mellitus: A case report and literature review.

RATIONALE: Gitelman syndrome (GS) is an uncommon autosomal recessive tubulopathy resulting from a functional deletion mutation in the SLC12A3 gene. Its onset is typically insidious and challenging to discern, and it is characterized by hypokalemia, metabolic alkalosis, and reduced urinary calcium excretion. There is limited literature on the diagnosis and management of GS in individuals with concomitant diabetes. PATIENT CONCERNS: A 36-year-old male patient with a longstanding history of diabetes exhibited suboptimal glycemic control. Additionally, he presented with concurrent findings of hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. DIAGNOSIS: Building upon the patient's clinical manifestations and extensive laboratory evaluations, we conducted thorough genetic testing, leading to the identification of a compound heterozygous mutation within the SLC12A3 gene. This definitive finding confirmed the diagnosis of GS. INTERVENTIONS: We have formulated a detailed medication regimen for patients, encompassing personalized selection of hypoglycemic medications and targeted electrolyte supplementation. OUTCOMES: Following 1 week of comprehensive therapeutic intervention, the patient's serum potassium level effectively normalized to 3.79 mmol/L, blood glucose parameters stabilized, and there was significant alleviation of clinical symptoms. LESSONS: GS has a hidden onset and requires early diagnosis and intervention based on patient related symptoms and laboratory indicators in clinical practice, and personalized medication plans need to be provided according to the specific situation of the patient.