Research Analysis of SLC12A3 Gene Mutation and Molecular Mechanism in Gitelman Syndrome / 罕见病研究

ObjectiveThis study aimed at conducting retrospective analysis of the clinical symptoms and genetic mutations in 20 children with Gitelman syndrome treated at the Affiliated Children′s Hospital of Nanjing Medical University from August 2015 to November 2022 and also explored the molecular mechanism of the pathogenic high-frequency mutation D486N in the Chinese population.MethodsWe collected the clinical manifestations, growth and development status, laboratory examination results, and SLC12A3 gene variations of the patients. We distinguished the wild-type and mutant SLC12A3 genes overexpressed in human embryonic kidney 293T cells (HEK293T). We used protein immunoblotting to detect the expression level of NCC, and used immunofluorescence techniques to examine the subcellular localization of NCC. In addition, we investigated the impact of the high-frequency SLC12A3 gene mutation D486N on NCC protein expression and localization.ResultsIn the 20 patients with Gitelman syndrome, all of them had hypokalemia. We indemnified twenty-six SLC12A3 gene mutations, 13 of which are missense mutation, 1 of which synonymous mutation, 1 nonsense mutation, 4 frameshift mutation, and 7 splicing site mutation. Among them, four mutations (p.T235K, c.1096-1G > A, p.A464A, and c.2660+1_2660+2insT) were novel mutations.ConclusionsWe found the preliminary evidence that the high-frequency mutation D486N in the Chinese population affected the expression of total and membrane-bound NCC protein and influenced the membrane localization of NCC protein. The findings of this study provides experimental evidence for genetic counseling, diagnosis, and treatment of Gitelman syndrome.

Adolescent Gitelman syndrome:a case report and literature review / 中国综合临床

Objective:To explore the clinical characteristics and genetics of a Chinese patient with Gitelman syndrome (GS) and improve the awareness and diagnosis of GS among clinicians.Methods:Retrospectively analyzed the GS patient's clinical feature, laboratory examination, diagnosis, treatment and literature review admitted to Hebei General Hospital in September 2022.Results:A twelve-year-old boy was admitted to our department due to weakness of lower limbs. Laboratory tests after admission showed hypokalemia, hypomagnesemia, hypocalcemia and metabolic alkalosis. Genetic testing showed tow compound heterozygous mutations in the SLC12A3 gene (c.1456G>A and c.634G>A), which ultimately diagnosed as GS. The patient is on the mend and allowed to leave the hospital after treated by potassium supplement.Conclusion:The rate of leak diagnosis is high. Genetic testing should be undergo earlier if the patients suspected GS.

Gitelman syndrome, a rare cause of refractory hypokalemia. A case report / Símdrome de Gitelman, causa rara de hipopotasemia refractaria. Reporte de caso

Abstract Introduction: Gitelman syndrome is a rare hereditary primary renal tubular disorder, with a prevalence of approximately 1 to 10 cases per 40 000 people. It does not have specific symptoms, so its diagnosis depends on high clinical suspicion by the treating physical and a sequential approach to hypokalemia, especially in young patients. Thus, a diagnostic algorithm is proposed at the end of this report. Case presentation: A 23-year-old woman with a history of hospitalization due to hypokalemia presented to the emergency service with intermittent cramping in her lower limbs, which was exacerbated by gastrointestinal symptoms. Laboratory tests reported the following findings: metabolic alkalosis, elevated levels of potassium, magnesium, chloride and sodium in urine, and reduced levels of calcium in urine. Thus, potassium supplementation and eplerenone administration were started, obtaining the complete resolution of symptoms. At her last follow-up appointment, the patient was asymptomatic, and her serum electrolyte levels were normal. In addition, during her hospital stay and due to the high suspicion of Gitelman syndrome, a genetic study was performed, which reported a mutation of the SCL12A3 gene, confirming the diagnosis. Conclusion: The sequential approach to a patient with recurrent hypokalemia is very important to reach an accurate diagnosis among a wide range of differential diagnoses.

Resumen Introducción. El síndrome de Gitelman es un trastorno tubular renal primario hereditario poco frecuente, con una prevalencia aproximada de 1 a 10 casos por cada 40 000 personas; su sintomatologia es inespecífica, por lo que su diagnóstico depende de la alta sospecha clínica por parte del médico tratante y de un abordaje secuencial de la hipopotasemia, sobre todo en pacientes jóvenes, para lo cual se propone un algoritmo diagnóstico al final de este reporte. Presentación de caso. Mujer de 23 años con antecedente de hospitalización por hipopotasemia, quien consultó por calambres musculares intermitentes en miembros inferiores, los cuales se agudizaron debido a síntomas gastrointestinales. En los exámenes de laboratorio se reportaron los siguientes hallazgos: alcalosis metabólica, niveles elevados de potasio, magnesio, cloro y sodio en orina, y niveles reducidos de calcio en orina, por lo que se inició suplementación de potasio y manejo con eplerenona, obteniéndose resolución completa de los síntomas. En su último control, la paciente se encontraba asintomática y sus niveles séricos de electrolitos eran normales. Además, durante la hospitalización, y debido a la alta sospecha de síndrome de Gitelman, se solicitó estudio genético que reportó mutación del gen SCL12A3, confirmándose el diagnóstico. Conclusión. El abordaje secuencial de un paciente con hipopotasemia recurrente es de gran importancia para realizar un diagnóstico certero ante una amplia gama de diagnósticos diferenciales.

Progress of SLC12 family related renal tubular disorders / 国际儿科学杂志

The ions transport in human cells plays a key role in maintaining normal physiological functions of cells, and the solute transporter(SLC)is responsible for most of the ions transport in somatic cells.The SLC12 family encodes electrically neutral cation-coupled chloride ion cotransporters, which are essential in maintaining intracellular and extracellular chloride balance and related cellular physiological processes.At present, there are 9 members of SLC12 family, and the expression and distribution of these family members are tissue-specific.They are distributed in renal tissues and mainly expressed in renal tubular epithelial cells, and their distribution and expression are significantly different, so their physiological roles in kidney are also different.This article will briefly review the physiological role of SLC12 family in kidney and related renal tubular diseases.

Whole-exome sequencing in diagnosing 2 cases of Gitelman syndrome / 中南大学学报(医学版)

Two patients with Gitelman syndrome were admitted to the Department of Endocrinology, Third Xiangya Hospital of Central South University. The genomic DNA from the patients' peripheral blood was extracted and the whole-exome sequencing was performed to detect the possible mutations. The function of the mutation sites was analyzed by bioinformatics software. Through whole-exome sequencing and Sanger sequencing, we have found that 2 patients with Gitelman syndrome carried compound heterozygous mutations of SLC12A3 gene, which were c.486_490delTACGGinsA, p.R943W, p.D486N, and p.R928C. Among them, c.486_490delTACGGinsA insertion deletion mutation causes frame shift and protein truncation. The p.R943W, p.D486N, and p.R928C of SLC12A3 gene were predicted to be pathogenic mutations by SIFT, PolyPhen2, and Mutation Taster. These 4 mutations were all reported, but p.R943W was first reported in Chinese population. Gitelman syndrome is rare in clinic and the rate of missed diagnosis is high. Early genetic analysis in patients with Gitelman syndrome is helpful to determine the etiology and guide the treatment.

Expert Consensus for the Diagnosis and Treatment of Gitelman Syndrome in China (2021) / 罕见病研究

@#In recent years, research on the clinical phenotypes, new classifications, modified functional tests, biomarkers and management experience for patients with Gitelman syndrome (GS)has made a lot of progress in China. Based on evidence-based medicine, this consensus summarizes aspects related to GS, including clinical manifestations and classification, diagnosis, treatment strategies, and management of chronic complica-tions and comorbidity. This consensus provides an important reference for the diagnosis and treatment of GS.

Hipokalemia de gradiente transtubular alto: una propuesta práctica para su enfoque / High transtubular gradient hypokalemia: a practical proposal for its focus

Resumen El potasio es un ion de predominio intracelular involucrado en múltiples funciones esenciales para mantener la homeostasis celular. Por lo anterior, sus concentraciones a nivel plasmático se encuentran estrechamente reguladas mediante el sistema renal y endocrino, además de estar afectado ante situaciones como la acidosis, cambios en la osmolaridad plasmática y concentración de otros electrolitos. La hipokalemia es un trastorno electrolítico común en la práctica clínica causado por el aporte inadecuado o pérdidas excesivas. Su enfoque diagnóstico requiere de una apropiada historia clínica que incluya antecedentes personales patológicos, farmacológicos, y un examen físico detallado con determinación del estado de volemia e hidratación del paciente, así como la medición de otros electrolitos a nivel plasmático y ocasionalmente en orina. El gradiente transtubular de potasio es una herramienta útil para direccionar posibles causas. Dentro de las causas de hipokalemia de gradiente transtubular elevado se encuentra el síndrome de Bartter.

Abstract Potassium is a predominantly intracellular ion involved in multiple essential functions to maintain cellular homeostasis. Therefore, its variations at the plasma level are tightly regulated by the renal and the endocrine systems; in addition to being affected by situations such as acidosis, changes in plasma osmolality and concentration of another electrolytes. Hypokalemia is a common electrolyte disorder in clinical practice affected by reporting excessive damage or loss. Its diagnostic approach requires a complete medical record that includes personal pathological and pharmacological information, a specific physical examination with certain conditions like patient's blood volume and hydration status, as well as the measurement of other electrolytes at the plasma level and occasionally in urine. The transtubular potassium gradient is a useful tool to address possible causes. Bartter syndrome is one of the causes of elevated transtubular gradient hypokalemia.

Diagnóstico de síndrome de Gitelman en paciente con condrocalcinosis / Diagnosis of gitelman syndrome in patient with condrocalcinosis

RESUMEN Introducción: El síndrome de Gitelman es una tubulopatía caracterizada por alcalosis metabólica hipopotasémica, hipomagnesemia e hipocalciuria. Sus efectos musculoesqueléticos son comunes, pudiendo provocar desarrollo de condrocalcinosis. Caso clínico: Paciente con condrocalcinosis de larga data asociada a hipomagnesemia crónica en tratamiento con calcio y magnesio. Tras la suspensión del tratamiento debido a una intervención quirúrgica presentó debilidad generalizada, alcalosis metabólica, hipopotasemia, hipomagnesemia e hipocalciuria con diagnóstico final de síndrome de Gitelman. Tras la instauración de tratamiento, mejoró clínica y analíticamente manteniendo cifras iónicas estables. Discusión y conclusiones: Resulta fundamental un adecuado diagnóstico de este tipo de tubulopatías, ya que un tratamiento adecuado evita complicaciones asociadas.

ABSTRACT Introduction: Gitelman syndrome is a renal tubule disease that involves hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. The musculoskeletal effects of Gitelman syndrome are common, including the development of chondrocalcinosis. Clinical case: A female patient with long-standing chondrocalcinosis associated with chronic hypomagnesaemia on treatment with calcium and magnesium. After the suspension of the treatment due to surgery, she presented with a generalised weakness, metabolic alkalosis, hypokalaemia, hypomagnesaemia and hypocalciuria, with final diagnosis of Gitelman syndrome. After re-introducing the treatment, she improved clinically, with electrolytes remaining stable. Discussion and conclusions: A proper diagnosis of this type of tubular diseases is essential because an adequate treatment avoids associated complications.

Síndrome de Gitelman / Gitelman syndrome

El síndrome de Gitelman forma parte de las denominadas tubulopatías perdedoras de sal. El bloqueo parcial de la reabsorción de sodio en el túbulo contorneado distal determina la aparición de hipokalemia e hipomagnesemia. Se realizó un estudio descriptivo de una serie de cinco casos de síndrome de Gitelman (4 mujeres, de 28 a 85 años de edad) atendidos en nuestra institución entre los años 2004 y 2015. La forma de diagnóstico más frecuente en nuestra serie fue por hallazgo de laboratorio. El único síntoma clínico manifestado en forma espontánea fue astenia. En cuanto a los valores de laboratorio, la potasemia fue 2.5 ± 0.5 mmol/l, con un valor mínimo de 2.1. Adicionalmente, el valor de magnesio en sangre fue 1.3 ± 0.3 mg/dl. Como conclusión, observamos que las formas de presentación consisten en alteraciones bioquímicas con o sin manifestaciones inespecíficas, lo que representa actualmente la mayor dificultad diagnóstica y refuerza la importancia de lograr un diagnóstico oportuno, en especial en pacientes jóvenes y con valores críticos de potasio sérico.

Gitelman syndrome is one of the salt losing tubulopathies. Hypokalemia and hypomagnesemia appear in the setting of the partial blockade of salt absorption in the distal tubule. We conducted a descriptive study of a case series of five patients with Gitelman syndrome (4 women, from 28 to 85 years) in our institution, between the years 2004 and 2015. The most frequent form of diagnosis in our series was by laboratory finding. The only acknowledged clinical symptom was malaise. Regarding laboratory findings, the mean potassemia was of 2.5 ± 0.5 mmol/l, with a minimum value of 2.1 mmol/l. Additionally, the serum magnesium value was of 1.3 ± 0.3 mg/dl. In conclusion, we observed that the forms of presentation consist of biochemical alterations with or without nonspecific manifestations, which currently represents the greatest diagnostic difficulty and reinforces the importance to achieve a timely diagnosis, especially in young patients with critical serum potassium values.

A novel heterozygous duplication of the SLC12A3 gene in two Gitelman syndrome pedigrees: indicating a founder effect

Gitelman syndrome is an autosomal recessive salt-wasting tubulopathy caused by mutations in the SLC12A3 gene. A female and a male sibling from two unrelated Greek-Cypriot families presenting with a severe salt-wasting tubulopathy dueto compound heterozygous mutations of a novel duplication and a previously reported missense mutation in the SLC12A gene are described. Sanger sequencing was used to identify possible mutations in the SLC12A3 gene. For the detection of duplications/conversions and deletions in the same gene, Multiplex ligation probe amplification (MLPA) analysis was performed. Direct sequencing and MLPA analysis of the SLC12A3 gene identified two compound heterozygous mutations in both unrelated probands. Both probands were identified to carry in compound heterozygosity the known p.Met581Lys and a novelheterozygous duplication of exons 9-14 (E9_E14dup). The diagnosis of Gitelman syndrome was made through clinical assessment, biochemical screening and genetic analysis. The identification of the novel SLC12A3 duplication seems to be characteristic of Greek-Cypriot patients and suggests a possible ancestral mutational event that has spread in Cyprus due to a possible founder effect. Testing for Gitelman syndrome probable variants can be performed before proceeding to a full gene sequencing dropping the diagnostic cost. In addition, this report adds to the mutational spectrum observed.

A case of Gitelman syndrome: our experience with a patient treated in clinical practice on a local island / Journal of Rural Medicine

Background: Gitelman syndrome (GS) is an autosomal recessive salt-losing renal tubulopathy resulting from mutations in the thiazide-sensitive Na-Cl cotransporter (NCC) gene. Notably, lack of awareness regarding GS and difficulty with prompt diagnosis are observed in clinical practice, particularly in rural settings.Case presentation: We report a case of a 48-year-old man with GS who presented to a local clinic on a remote island. Occasional laboratory investigations incidentally revealed a reduced serum potassium level of 2.6 mmol/L. A careful medical interview revealed episodes of intermittent paralysis of the lower extremities and muscular weakness for >30 years. Subsequent laboratory investigations revealed hypomagnesemia, hypocalciuria, and hypokalemic metabolic alkalosis. Based on the patient’s history, clinical presentation, and laboratory investigations, we suspected GS. Genetic testing revealed a rare homozygous in-frame 18 base insertion in the NCC gene that might have resulted from the founder effect, consequent to his topographically isolated circumstances.Conclusion: More case studies similar to our study need to be added to the literature to gain a deeper understanding of the functional consequences of this mutation and to establish optimal management strategies for this condition, particularly in rural clinical settings.

Wilson Disease Comorbid with Hereditary Sensory Autonomic Neuropathy Type IV and Gitelman Syndrome / 대한소아소화기영양학회지

Wilson disease a rare autosomal recessive inherited disorder of copper metabolism, is characterized by excessive deposition of copper in the liver, brain, and other tissues. Wilson disease is often fatal if it is not recognized early and treated when it is symptomatic. Gitelman syndrome is also an autosomal recessive kidney disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. Hereditary sensory autonomic neuropathy type IV (HSAN-IV), a very rare condition that presents in infancy, is characterized by anhidrosis, absence of pain sensation, and self-mutilation. It is usually accompanied by developmental delay and mental retardation. We report a case of Wilson disease manifested as fulminant hepatitis, acute pancreatitis, and acute kidney injury in a 15-year-old boy comorbid with HSAN-IV and Gitelman syndrome. Such concurrence of three genetic diseases is an extremely rare case.

Research advances in hypokalemic salt-losing tubulopathies / 上海交通大学学报（医学版）

Hereditary tubular disorders play an important role in the ion transport mechanism of kidney. Hypokalemic salt-losing tubulopathies (SLTs) are a set of rare hereditary diseases, which accompany with hypokalaemic metabolic alkalosis, normo or hypotension, and are associated with high plasma renin activity and hyperaldosteronemia. Bartter syndrome and Gitelman syndrome, characterized by the disability of the thick ascending limb of Henle's loop and/or the distal convoluted tubule, respectively, are two common types of SLTs. Some types of SLTs share similar clinical manifestations, making them difficult to diagnose. Besides, with the development of molecular genetics, new disease-causing genes have been discovered. It's inconvenient for clinicians to refer to the old classification of SLTs. The review mainly covered the newly discovered pathogenic genes of SLTs and the corresponding pathogenic mechanisms. In addition, a new system for classification of SLTs based on physiology and pharmacology was introduced.

Progress of diagnosis and treatment for Gitelman syndrome and cystinosis / 中华实用儿科临床杂志

Gitelman syndrome(GS) is an autosomal recessive,salt-losing tubulopathy resulted from inactivating mutations in the SLCl2A3 gene that encodes the Thiazine diuretic sensitive sodium chloride cotransporter (NCCT).GS is characterized by hypokalemic metabolic alkalosis,hypomagnesemia and hypocalciuria.Diagnosis of GS is relied on the clinical symptoms,biochemical abnormalities and genetic test.All GS patients are suggested to keep high-sodium diet.Magnesium and potassium supplements are usually given to GS patients for lifelong to improve clinical symptoms.Individual management of GS includes health education,complication evaluation and regular follow-up with annual evaluation by a nephrologist.Cystinosis is a rare autosomal-recessive lysosomal storage disease caused by inactivating mutations in the CTNS gene that encodes the lysosomal cystine transporter,cystinosin,resulting in the accumulation of cystine within the lysosome.There are 3 clinical forms of cystinosis:infantile or early-onset nephropathic cystinosis,juvenile or late-onset nephropathic cystinosis and adult or ocular cystinosis.Diagnosis of cystinosis is based on the CTNS genetic test.Early diagnosis and early cystine-depleting therapy with cysteamine is essential to prevent or attenuate end-organ damage and improve overall prognosis.

Persistent severe hypokalemia: Gitelman syndrome and differential diagnosis / Hipocalemia grave persistente: Síndrome de Gitelman e diagnósticos diferenciais

Abstract The main causes of hypokalemia are usually evident in the clinical history of patients, with previous episodes of vomiting, diarrhea or diuretic use. However, in some patients the cause of hypokalemia can become a challenge. In such cases, two major components of the investigation must be performed: assessment of urinary excretion potassium and the acid-base status. This article presents a case report of a patient with severe persistent hypokalemia, complementary laboratory tests indicated that's it was hypomagnesaemia and hypocalciuria associated with metabolic alkalosis, and increase of thyroid hormones. Thyrotoxic periodic paralysis was included in the differential diagnosis, but evolved into euthyroid state, persisting with severe hypokalemia, which led to be diagnosed as Gitelman syndrome.

Resumo As principais causas de hipocalemia normalmente são evidentes na história clínica dos pacientes em investigação etiológica, com episódios prévios de vômitos, diarréia ou uso de diuréticos. Entretanto, em alguns pacientes, a causa da hipocalemia pode se tornar um desafio. Em tais casos, dois principais componentes da investigação devem ser realizados: avaliação da excreção do potássio urinário e do "status" ácido-básico. Este artigo traz um relato de caso de uma paciente portadora de hipocalemia grave persistente, com investigação laboratorial complementar caracterizada por hipomagnesemia e hipocalciúria, associada à alcalose metabólica e elevação dos hormômios tireoideanos. A apresen- tação inicial do quadro incluiu paralisia periódica tireotóxica como um dos principais diagnósticos diferenciais, porém, a paciente evoluiu para um es- tado eutireoideo e persistiu com grave hipocalemia, sendo, por fim, realizado diagnóstico clínico de Síndrome de Gitelman.

Rheumatoid arthritis accompanied by Gitelman syndrome / 영남의대학술지

Gitelman syndrome is a condition caused by a mutation of the thiazide sensitive Na-Cl cotransporter gene on the distal convoluted tubule. It results in a variety of clinical features, including hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. It is often diagnosed in asymptomatic adults presented with unexplained hypokalemia; however, it is sometimes associated with muscular cramps, numbness, fatigue, weakness, or paralysis. We experienced a case of rheumatoid arthritis accompanied by Gitelman syndrome, presented with hand tremor. We diagnosed her using renal clearance study and genetic analysis. Here, we report our experiences regarding this case along with a literature review.

Gitelman's syndrome with osteoarthrosis: a case report / 天津医药

Gitelman's syndrome (GS) is an autosomal recessive hereditary tubulopathy.It is caused by sodium reabsorption in the distal convoluted tubule of the renal unit,which is not yet fully cured.It is characterized by great heterogeneity with clinical manifestations.Some patients with no symptoms,were confirmed by hypokalemia with physical examination.The others can be manifested as fatigue,nocturia,polydipsia and hypotension.Less literature is reported about GS combined with osteoarthrosis.In this report,the author reported a patient of GS with osteoarthrosis characterized by hypokalemia,hypomagnesemia,metabolic alkalosis,lower blood pressure,and swelling and pain in left knee joint.The symptoms were improved after treatment with potassium and magnesium supplementation

Gitelman syndrome caused by SLC12A3 gene mutations: a report of pedigree analysis / 临床儿科杂志

Objective To explore the gene diagnosis of Gitelman syndrome.Methods The clinical data of a child with Gitelman syndrome were retrospectively analyzed along with gene detection results of his elder sister and parents.Results A 6-year-old boy was hospitalized for fever and hypokalemia.Gene detection of SLC12A found a new locus mutation of EXON21 c.2522A＞G p.(Asp841Gly) and a heterozygosis of EXON16 c.1946C＞T p.(Thr649Met).The diagnosis of Gitelman syndrome was confirmed.His mother carried a heterozygosis mutation of EXON21 c.2522A＞G p.(Asp841Gly),while his father and elder sister carried a heterozygosis mutation of EXON16 c.1946C＞T p.(Thr649Met).Conclusion Gene detection of SLC12A is helpful in the diagnosis of Gitelman syndrome.The newly discovered mutation of SLC12A3 gene has enriched the mutation spectrum of Gitelman syndrome.

Genotype, phenotype, and follow-up of Chinese patients with Gitelman's syndrome / 中华内分泌代谢杂志

Objective To analyze the characteristics of the genotype, phenotype, and follow-up of Gitelman's syndrome (GS) in the largest group of Chinese patients. Methods Sixty seven patients with GS underwent SLC12A3 gene analysis. Clinical characteristics and biochemical findings at the first presentation as well as follow-up were reviewed. Additionally, the associations of genotypes and phenotypes were explored. Results Forty-one different SLC12A3 mutations were identified in 67 patients with GS, including 11 novel ones, and 5 recurrent ones. 3 families (5. 7% ) had triple SLC12A3 mutations. Typical hypocalciuria and hypomagnesemia were not found in 6(9% ) and 8 (11. 9% )patients, respectively. In addition, male patients had an earlier age of onset and a higher urinary fraction excretion of electrolytes. 2 patients presented with chronic kidney disease, 13 (19. 4% ) with type 2 diabetes, 14 (20. 9% )with impaired glucose tolerance, and 5(7. 5% ) with impaired fasting glucose. Conclusion This study revealed 41 mutations in 67 Chinese patients with GS, including 11 novel variants and 5 high-frequency ones. Fraction excretion of electrolyte in urine may be more sensitive in the evaluation of phenotype compared with those of blood. It is difficult to correct hypokalemia and hypomagnesemia in GS. Patients with GS are at higher risk of the development of diabetes than ordinary people.

Gitelman syndrome: From pathophysiology to clinical practice / 国际药学研究杂志

Normal tubular transport function is important for maintaining the volume of fluid and electrolyte in the body. Advances in molecular biology have revealed the genetic regulation and pathophysiological mechanisms of inherited tubular disorders. This progress not only sheds some light on the clinical practice, but also leads to better understanding of the normal tubular structures and function. As the most common inherited tubular disorders, Gitelman syndrome (GS) is an autosomal recessive inherited disease, mainly caused by loss-of-function mutations in the SLC12A3 gene encoding the sodium-chloride co-transporter (NCC) in the distal convoluted tubule. This review summarizes some of the recent progress in genetic diagnosis, in vivo and in vitro functional studies and management of GS.