Minigene splicing assays reveal new insights into exonic variants of the SLC12A3 gene in Gitelman Syndrome.

Gitelman syndrome (GS) is a kind 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 exonic variants disrupt normal pre-mRNA splicing, has been related to a variety of diseases. 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. 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.

Unmasking of Gitelman Syndrome during Pregnancy in an Adolescent with Thyrotoxic Crisis

Background. Gitelman syndrome (GS) is an inherited salt-losing renal tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. Patients can be asymptomatic until late adolescence or adulthood, and hence may be discovered incidentally during presentation with other illnesses. GS has been described in association with thyroid disorders and should be considered in patients with hyperthyroidism and persistent hypokalemia, especially in those with associated hypomagnesemia and hypocalciuria. Case summary. In this report, we describe an 18-year-old female who presented with hyperemesis gravidarum and thyrotoxicosis, and was incidentally found to have GS, confirmed by the sequence analysis of SLC12A3. Conclusions. Thyroid dysfunctions, such as hypothyroidism, thyrotoxicosis, and thyroid nodules, may develop during pregnancy. A structural homology between the beta-human chorionic gonadotropin and thyroid stimulating hormone molecules, as well as their receptors is probably the basis for the transient thyrotoxicosis crisis during pregnancy. Since hyperemesis in pregnancy can also lead to hypokalemia and alkalosis, a high index of suspicion for GS during pregnancy is required for timely diagnosis and management.

Case report: Gitelman Syndrome With Type 2 Diabetes Caused by a New Homozygous Mutation of SLC12A3 (c.1567G>A) and Family Follow-up

Background: This case reports Gitelman syndrome combined with type 2 diabetes caused by a new homozygous mutation in the SLC12A3 (c.1567G>A) gene. This is the first report in Asia. The patient's family has 10 biological siblings. We have further tested the SLC12A3 gene in the patient's family, revealing the genetic characteristics.Case presentation: The main symptoms of this patient were long-term dizziness, weakness of the limbs, insomnia and anxiety, laboratory examinations found elevated fasting blood sugar, hypomagnesemia, increased urinary calcium, slightly increased RAAS activity, and hypokalemia that is difficult to correct. Potassium and magnesium were supplemented by oral potassium chloride sustained-release tablets and potassium-magnesium aspartate oral solution. The patient controlled blood glucose only through exercise and diet. After three months, the patient still occasionally experienced dizziness, the symptoms of fatigue were significantly relieved, the serum potassium was slightly decreased, the serum magnesium was normal, and the patient's fasting blood glucose was slightly increased. In family tracing, the heterozygous mutation site of SLC12A3 (C.1567g >A) was detected in the patient's mother, two sisters and one brother, but no obvious symptoms were presented. We followed up their situation through telephone follow-up.Conclusion: In this case, we found that Gitelman syndrome homozygous variants had more severe clinical phenotypes, and that hypokalemia and hypomagneemia were more difficult to correct. When serum potassium and magnesium concentrations tended to be normal, patients had better glycemic control. Some SLC12A3 mutation carriers may have atypical clinical symptoms and normal serum potassium, which is worthy of clinical attention.

The Diagnosis Algorithm of Chronic Hypokalemia in Bartter Syndrome and Gitelman Syndrome: A Case Report

Introduction: Hypokalemia is common disorder characterized by low plasma potassium levels (<3.5 mEq / L). Hypokalemia can be caused by genetic disorders. Bartter syndrome and Gitelman syndrome are rare genetic disorders that cause damage to the tubular kidneys. The cause of hypokalemia must be determined by analyzing the diagnosis algorithm of hypokalemia. Case Illustration: A 27-year-old woman was brought to the emergency room with complaints of weakness in both legs since 1 day ago. Obtained a history of chronic hypokalemia since 5 years ago. No history of thyroid disease, and never taking diuretic drugs. The patient is calm. Vital signs: BP: 110/60, regular pulse 88x/minute, temperature: 36.7°C, respiratory rate 14x/minute, oxygen saturation 99% in room air. ECG showed Normal sinus rhythm with normal T wave. Laboratory findings showed severe hypokalemia with plasma potassium 1.7 mEq/L, increased urine potassium (71.1 mmol/24 hours), increased urine sodium 306 mmol/24 hours, and increased urine chloride (342 mmol/24 hours), plasma magnesium levels were normal (1.91 mg/dL). KCl infusion was given to correct electrolyte imbalance condition. Discussion: : Several examinations must be performed to confirm the cause of hypokalemia condition. The diagnosis of this patient was suspected to lead to Bartter syndrome and Gitelman syndrome, because there was an increase in urinary potassium excretion, normotensive conditions, no suspicion of metabolic acidosis, and no symptoms of nausea and vomiting and no history of diuretic drugs usage. Keywords: Hypokalemia, Bartter syndrome, Gitelman syndrome