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1.
Am J Physiol Renal Physiol ; 319(6): F1043-F1053, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33135481

RESUMEN

The genetic disease Gitelman syndrome, knockout mice, and pharmacological blockade with thiazide diuretics have revealed that reduced activity of the NaCl cotransporter (NCC) promotes renal Mg2+ wasting. NCC is expressed along the distal convoluted tubule (DCT), and its activity determines Mg2+ entry into DCT cells through transient receptor potential channel subfamily M member 6 (TRPM6). Several other genetic forms of hypomagnesemia lower the drive for Mg2+ entry by inhibiting activity of basolateral Na+-K+-ATPase, and reduced NCC activity may do the same. Lower intracellular Mg2+ may promote further Mg2+ loss by directly decreasing activity of Na+-K+-ATPase. Lower intracellular Mg2+ may also lower Na+-K+-ATPase indirectly by downregulating NCC. Lower NCC activity also induces atrophy of DCT cells, decreasing the available number of TRPM6 channels. Conversely, a mouse model with increased NCC activity was recently shown to display normal Mg2+ handling. Moreover, recent studies have identified calcineurin and uromodulin (UMOD) as regulators of both NCC and Mg2+ handling by the DCT. Calcineurin inhibitors paradoxically cause hypomagnesemia in a state of NCC activation, but this may be related to direct effects on TRPM6 gene expression. In Umod-/- mice, the cause of hypomagnesemia may be partly due to both decreased NCC expression and lower TRPM6 expression on the cell surface. This mini-review discusses these new findings and the possible role of altered Na+ flux through NCC and ultimately Na+-K+-ATPase in Mg2+ reabsorption by the DCT.


Asunto(s)
Síndrome de Gitelman/metabolismo , Túbulos Renales Distales/metabolismo , Magnesio/metabolismo , Eliminación Renal , Reabsorción Renal , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Animales , Calcineurina/metabolismo , Síndrome de Gitelman/genética , Síndrome de Gitelman/fisiopatología , Humanos , Túbulos Renales Distales/fisiopatología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Canales Catiónicos TRPM/metabolismo , Uromodulina/metabolismo
3.
Nephrol Ther ; 16(4): 233-243, 2020 Jul.
Artículo en Francés | MEDLINE | ID: mdl-32622651

RESUMEN

Bartter-Gitelman syndromes are rare inherited autosomal recessive salt-losing tubulopathies characterized by severe and chronic hypokalemia associated with metabolic alkalosis and secondary hyperaldosteronism. Bartter syndrome results from a furosemide-like defect in sodium reabsorption in the Henle's loop leading to hypercalciuria and defect in urinary concentration capacity. The antenatal Bartter syndrome is defined by polyhydramnios and an infantile polyuria with severe dehydration whereas classic Bartter syndrome appears during childhood or adulthood. Gitelman syndrome is a thiazide-like salt-losing tubulopathy. It is associated with hypomagnesemia, hypocalciuria without defect in urinary concentration capacity. The diagnosis is most often made in adolescents or adults. Clinical symptoms include tetany, delay in the height-weight growth curves, chronic tiredness, muscle weakness, myalgia and vertigo. Nephrocalcinosis in Bartter syndrome could lead to chronic kidney disease. Antenatal Bartter syndrome requires hospitalization in intensive care unit to manage the severe newborn dehydration. Chondrocalcinosis is the major complication in the Gitelman syndrome. The corner stones of treatment is the fluid and electrolyte management Bartter and Gitelman syndromes need lifelong oral supplementations of potassium, salt (Bartter) and magnesium (Gitelman). Indomethacin is efficient to reduce water and electrolyte loss in Bartter. In Gitelman, potassium-sparing diuretics may be helping for severe hypokaliemia but they will reinforce hypovolemia.


Asunto(s)
Síndrome de Bartter , Síndrome de Gitelman , Síndrome de Bartter/complicaciones , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/fisiopatología , Síndrome de Bartter/terapia , Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/fisiopatología , Síndrome de Gitelman/terapia , Humanos
4.
Medicine (Baltimore) ; 99(29): e21123, 2020 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-32702863

RESUMEN

INTRODUCTION: Gitelman syndrome (GS) is an autosomal-recessive disease caused by SLC12A3 gene mutations. It is characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Recently, patients with GS are found at an increased risk for developing type 2 diabetes mellitus (T2DM). However, diagnosis of hyperglycemia in GS patients has not been thoroughly investigated, and family studies on SLC12A3 mutations and glucose metabolism are rare. Whether treatment including potassium and magnesium supplements, and spironolactone can ameliorate impaired glucose tolerance in GS patients, also needs to be investigated. PATIENT CONCERNS: We examined a 55-year-old Chinese male with intermittent fatigue and persistent hypokalemia for 17 years. DIAGNOSES: Based on the results of the clinical data, including electrolytes, oral glucose tolerance test (OGTT), and genetic analysis of the SLC12A3 gene, GS and T2DM were newly diagnosed in the patient. Two mutations of the SLC12A3 gene were found in the patient, one was a missense mutation p.N359K in exon 8, and the other was a novel insert mutation p.I262delinsIIGVVSV in exon 6. SLC12A3 genetic analysis and OGTT of 9 other family members within 3 generations were also performed. Older brother, youngest sister, and son of the patient carried the p.N359K mutation in exon 8. The older brother and the youngest sister were diagnosed with T2DM and impaired glucose tolerance by OGTT, respectively. INTERVENTIONS: The patient was prescribed potassium and magnesium (potassium magnesium aspartate, potassium chloride) oral supplements and spironolactone. The patient was also suggested to maintain a high potassium diet. Acarbose was used to maintain the blood glucose levels. OUTCOMES: The electrolyte imbalance including hypokalemia and hypomagnesemia, and hyperglycemia were improved with a remission of the clinical manifestations. CONCLUSION: GS is one of the causes for manifestation of hypokalemia. SLC12A3 genetic analysis plays an important role in diagnosis of GS. Chinese male GS patients characterized with heterozygous SLC12A3 mutation should be careful toward occurrence of T2DM. Moreover, the patients with only 1 SLC12A3 mutant allele should pay regular attention to blood potassium and glucose levels. GS treatment with potassium and magnesium supplements, and spironolactone can improve impaired glucose metabolism.


Asunto(s)
Diabetes Mellitus Tipo 2/etiología , Síndrome de Gitelman/complicaciones , Hipopotasemia/etiología , Diabetes Mellitus Tipo 2/fisiopatología , Fatiga/etiología , Síndrome de Gitelman/fisiopatología , Humanos , Hipopotasemia/fisiopatología , Masculino , Persona de Mediana Edad , Mutación/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/genética
5.
Genes Genomics ; 42(9): 1035-1040, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32712837

RESUMEN

BACKGROUND: Gitelman syndrome (GS) is a tubulopathy characterized by hypokalemia, hypomagnesemia, hypocalciuria and metabolic alkalosis, which is caused by mutations in SLC12A3 gene. OBJECTIVE: The objective of this study was to investigate the mutation of SLC12A3 gene in a pedigree with GS and analyzed the clinical manifestations. METHODS: Next-generation sequencing and Sanger sequencing were performed to explore the mutations of SLC12A3 gene in a GS pedigree that included a 59-year-old male GS patient and a total of 11 family members within three generations. RESULTS: A novel compound heterozygous mutation of SLC12A3 gene (c.1712T > C in exon14 and c.2986_2987ins GCT in exon26) was identified by genetic testing in the proband. Moreover, we demonstrated that two brothers shared the same heterozygous mutation with the proband, but only one brother had the GS related symptoms. His nephew was the carrier of one mutation (c.1712T > C), and one of his brother, his sister and niece were carriers of the other (c.2986_2987ins GCT). CONCLUSIONS: This is the first study to report the novel pathogenic compound heterozygous mutation of SLC12A3 gene in GS. Our result further supports the lack of phenotype-genotype correlations in GS. Further functional studies are required to investigate pathophysiologic mechanisms of GS.


Asunto(s)
Síndrome de Gitelman/genética , Adulto , Familia , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Síndrome de Gitelman/fisiopatología , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipopotasemia/etiología , Hipopotasemia/genética , Masculino , Persona de Mediana Edad , Mutación , Linaje , Fenotipo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo
6.
BMC Nephrol ; 21(1): 256, 2020 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-32631286

RESUMEN

BACKGROUND: Renal loss of potassium (K+) and magnesium (Mg2+) in salt losing tubulopathies (SLT) leads to significantly reduced Quality of Life (QoL) and higher risks of cardiac arrhythmia. The normalization of K+ is currently the most widely accepted treatment target, however in even excellently designed RCTs the increase of K+ was only mild and rarely normalized. These findings question the role of K+ as the ideal marker of potassium homeostasis in SLT. Aim of this hypothesis-generating study was to define surrogate endpoints for future treatment trials in SLT in terms of their usefulness to determine QoL and important clinical outcomes. METHODS: Within this prospective cross-sectional study including 11 patients with SLTs we assessed the biochemical, clinical and cardiological parameters and their relationship with QoL (RAND SF-36). The primary hypothesis was that QoL would be more dependent of higher aldosterone concentration, assessed by the transtubular-potassium-gradient (TTKG). Correlations were evaluated using Pearson's correlation coefficient. RESULTS: Included patients were mainly female (82%, mean age 34 ± 12 years). Serum K+ and Mg2+ was 3.3 ± 0.6 mmol/l and 0.7 ± 0.1 mmol/l (mean ± SD). TTKG was 9.5/3.4-20.2 (median/range). While dimensions of mental health mostly correlated with serum Mg2+ (r = 0.68, p = 0.04) and K+ (r = 0.55, p = 0.08), better physical health was associated with lower aldosterone levels (r = -0.61, p = 0.06). TTKG was neither associated with aldosterone levels nor with QoL parameters. No relevant abnormalities were observed in neither 24 h-ECG nor echocardiography. CONCLUSIONS: Hyperaldosteronism, K+ and Mg2+ were the most important parameters of QoL. TTKG was no suitable marker for hyperaldosteronism or QoL. Future confirmatory studies in SLT should assess QoL as well as aldosterone, K+ and Mg2+.


Asunto(s)
Síndrome de Bartter/fisiopatología , Síndrome de Gitelman/fisiopatología , Hiperaldosteronismo/fisiopatología , Hipopotasemia/fisiopatología , Magnesio/metabolismo , Calidad de Vida , Adulto , Aldosterona/metabolismo , Síndrome de Bartter/metabolismo , Síndrome de Bartter/psicología , Femenino , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/psicología , Homeostasis , Humanos , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/psicología , Hipopotasemia/metabolismo , Hipopotasemia/psicología , Masculino , Persona de Mediana Edad , Potasio/metabolismo , Estudios Prospectivos , Desequilibrio Hidroelectrolítico/metabolismo , Desequilibrio Hidroelectrolítico/fisiopatología , Desequilibrio Hidroelectrolítico/psicología , Adulto Joven
7.
Nephrology (Carlton) ; 25(10): 749-757, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32542819

RESUMEN

AIM: Gitelman syndrome (GS) is a rare inherited salt-losing renal tubulopathy. Data on clinical features and the pregnancy outcome for female GS patients in a large cohort are lacking. The study was aimed to explore the phenotype and pregnant issue for female GS patients. METHODS: GS cases from the National Rare Diseases Registry System of China (NRSC) were collected, and detailed clinical, laboratory and genetic data were analysed. Articles on pregnancy in GS were also systemically reviewed. RESULTS: A total of 101 GS patients were included; among them, 42.6% were female and 79.2% showed hypomagnesaemia. A lower proportion of female patients presented before 18 years of age, with less frequently reported polyuria, higher serum potassium and less urine sodium and chloride excretions. There was no gender difference in the sodium-chloride cotransporter (NCC) dysfunction evaluated by hydrochlorothiazide test. Twelve of the 43 female GS patients delivered after disease symptom onset, and their pregnancies were generally uneventful. As a group, pregnant GS patients had lower potassium levels in the first-trimester (P = .002) requiring higher potassium supplementation. After delivery, serum potassium (P = .02) and magnesium (P = .03) increased significantly. Both caesarean section and vaginal delivery were safe. CONCLUSION: Female GS patients may have a less severe phenotype with generally favourable outcomes of pregnancy. Intensive monitoring and increased potassium supplementation are necessary during pregnancy, especially in the first-trimester.


Asunto(s)
Parto Obstétrico , Síndrome de Gitelman , Potasio , Complicaciones del Embarazo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Desequilibrio Hidroelectrolítico , Adulto , China/epidemiología , Cloruros/orina , Parto Obstétrico/métodos , Parto Obstétrico/estadística & datos numéricos , Femenino , Síndrome de Gitelman/epidemiología , Síndrome de Gitelman/genética , Síndrome de Gitelman/fisiopatología , Síndrome de Gitelman/terapia , Humanos , Recién Nacido , Magnesio/sangre , Masculino , Mutación , Poliuria/diagnóstico , Poliuria/etiología , Potasio/sangre , Potasio/uso terapéutico , Embarazo , Complicaciones del Embarazo/epidemiología , Complicaciones del Embarazo/etiología , Complicaciones del Embarazo/fisiopatología , Complicaciones del Embarazo/terapia , Resultado del Embarazo/epidemiología , Eliminación Renal/genética , Sodio/orina , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Desequilibrio Hidroelectrolítico/sangre , Desequilibrio Hidroelectrolítico/etiología , Desequilibrio Hidroelectrolítico/terapia , Desequilibrio Hidroelectrolítico/orina
8.
Nephrol Dial Transplant ; 35(11): 1901-1908, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31369102

RESUMEN

BACKGROUND: In rodents, the stimulation of adrenal progesterone is necessary for renal adaptation under potassium depletion. Here, we sought to determine the role of progesterone in adrenal adaptation in potassium-depleted healthy human volunteers and compared our findings with data collected in patients with Gitelman syndrome (GS), a salt-losing tubulopathy. METHODS: Twelve healthy young men were given a potassium-depleted diet for 7 days at a tertiary referral medical centre (NCT02297048). We measured by liquid chromatography coupled to tandem mass spectroscopy plasma steroid concentrations at Days 0 and 7 before and 30 min after treatment with tetracosactide. We compared these data with data collected in 10 GS patients submitted to tetracosactide test. RESULTS: The potassium-depleted diet decreased plasma potassium in healthy subjects by 0.3 ± 0.1 mmol/L, decreased plasma aldosterone concentration by 50% (P = 0.0332) and increased plasma 17-hydroxypregnenolone concentration by 45% (P = 0.0232) without affecting other steroids. CYP17 activity, as assessed by 17-hydroxypregnenolone/pregnenolone ratio, increased by 60% (P = 0.0389). As compared with healthy subjects, GS patients had 3-fold higher plasma concentrations of aldosterone, 11-deoxycortisol (+30%) and delta 4-androstenedione (+14%). Their post-tetracosactide progesterone concentration was 2-fold higher than that of healthy subjects and better correlated to plasma potassium than to plasma renin. CONCLUSION: The increase in 17-hydroxypregnenolone concentration after mild potassium depletion in otherwise healthy human subjects suggests that 17 hydroxylation of pregnenolone prevents the increase in progesterone observed in potassium-depleted mice. The unexpected over-response of non-mineralocorticoid steroids to tetracosactide in GS subjects suggests that the adrenal system not only adapts to sodium depletion but may also respond to hypokalaemia.


Asunto(s)
Glándulas Suprarrenales/fisiología , Síndrome de Gitelman/fisiopatología , Potasio/metabolismo , Progesterona/sangre , Adolescente , Adulto , Anciano , Aldosterona/sangre , Animales , Estudios de Casos y Controles , Cromatografía Liquida/métodos , Femenino , Síndrome de Gitelman/sangre , Humanos , Masculino , Ratones , Persona de Mediana Edad , Renina/sangre , Esteroides/sangre , Espectrometría de Masas en Tándem/métodos , Adulto Joven
10.
Iran J Kidney Dis ; 13(6): 417-418, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31880589

RESUMEN

Sheehan syndrome (SS) is postpartum hypopituitarism resulting from pituitary gland necrosis caused by severe hypotension due to massive intra or post-partum hemorrhage. Defective NaCl transport in the distal convoluted tubule, due to mutations affecting the thiazide sensitive Na-Cl-cotransporter results in the autosomal recessive salt-losing renal tubulopathy, Gitelman syndrome (GS). These two have been rarely described together. We report the case of a middle-aged woman with both these conditions, resulting in management issues. Physicians encountering unexplained hypokalemia refractory to standard management must consider the possibility of renal tubular disorders.


Asunto(s)
Síndrome de Gitelman/diagnóstico , Hipopotasemia/etiología , Hipopituitarismo/diagnóstico , Adulto , Comorbilidad , Diagnóstico Diferencial , Femenino , Síndrome de Gitelman/fisiopatología , Humanos , Hipopituitarismo/fisiopatología
11.
J Endocrinol Invest ; 41(3): 351-356, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28840514

RESUMEN

PURPOSE: Gitelman's syndrome (GS) presents normo-hypotension and absence of cardiovascular-renal remodeling despite high angiotensin II (Ang II), activation of renin-angiotensin-aldosterone system and is a human model of endogenous antagonism of Ang II signaling, opposite to hypertension. GS's clinical presentation leads to questions regarding what features might be responsible. One area of investigation involves Ang II signaling. In hypertensive patients, RhoA/Rho kinase (RhoA/ROCK) pathway activation by Ang II is involved in hypertension development/maintenance and induction of long-term consequences (cardiovascular-renal remodeling), while GS has reduced p63RhoGEF gene and protein levels and ROCK activity. Ang II signaling is mediated by Gαq, which interacts with p63RhoGEF via the α6-αN linker connecting p63RhoGEF's DH and PH domains acting as a conformational switch to activate RhoA/ROCK signaling. METHODS: We have investigated in GS patients, the presence of mutations in either p63RhoGEF's α6-αN linker domain and in Gαq's Ala253, Trp263, and Tyr356 residues, crucial for p63RhoGEF-Gαq interplay. RESULTS: No mutations have been found in specific aminoacids of p63RhoGEF α6-αN linker and Gαq, key for p63RhoGEF/Gαq interplay. CONCLUSIONS: Gitelman's syndrome normo/hypotension and lack of cardiovascular-renal remodeling are not due to mutations of p63RhoGEF α6-αN linker and Gαq interactions. This opens the way for investigations on different coding and no-coding regions (p63RhoGEF and Gαq promoters) and on altered transcriptional/post-transcriptional regulation. Clarification of how these biochemical/molecular mechanisms work/interact would provide insights into mechanisms involved in the GS's Ang II signaling fine tuning, in human physiology/pathophysiology in general and could also identify significant targets for intervention in the treatments of hypertension.


Asunto(s)
Síndrome de Gitelman/fisiopatología , Hipertensión/fisiopatología , Mutación , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Pronóstico , Factores de Intercambio de Guanina Nucleótido Rho/genética , Transducción de Señal , Proteína de Unión al GTP rhoA/genética
12.
Int Urol Nephrol ; 50(1): 91-96, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28744758

RESUMEN

Gitelman syndrome is the most common inherited tubular disease resulting from mutations of the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter in the early distal convoluted tubules. The review presents the underlying pathophysiologic mechanisms of acid-base and electrolyte abnormalities observed in patients with Gitelman syndrome. The syndrome is usually characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Additionally, increased chloride excretion and renin/aldosterone levels, hypophosphatemia (occasionally), hyponatremia (rarely) and glucose intolerance/insulin resistance have been reported. The knowledge of the pathophysiologic mechanisms is useful for the treatment of patients with Gitelman syndrome as well as for the understanding of other tubular diseases.


Asunto(s)
Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/fisiopatología , Hipopotasemia/etiología , Acidosis/etiología , Calcio/orina , Cloruros/orina , Humanos , Hipopotasemia/orina , Hiponatremia/etiología , Potasio/orina
13.
J Am Soc Nephrol ; 29(3): 727-739, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29237739

RESUMEN

Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle's loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.


Asunto(s)
Síndrome de Bartter/genética , Síndrome de Fanconi/genética , Síndrome de Gitelman/genética , Túbulos Renales/fisiopatología , Reabsorción Renal , Proteínas Transportadoras de Solutos/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Antígenos de Neoplasias/genética , Síndrome de Bartter/fisiopatología , Niño , Preescolar , Síndrome de Fanconi/fisiopatología , Síndrome de Gitelman/fisiopatología , Humanos , Lactante , Recién Nacido , Reabsorción Renal/genética , Cloruro de Sodio/metabolismo
14.
BMC Nephrol ; 18(1): 38, 2017 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-28125972

RESUMEN

BACKGROUND: Gitelman syndrome (GS) is an autosomal recessive renal tubular disorder characterised by renal salt wasting with hypokalaemia, metabolic alkalosis, hypomagnesaemia and hypocalciuria. It is caused by mutations in SLC12A3 encoding the sodium-chloride cotransporter on the apical membrane of the distal convoluted tubule. We report a South African family with five affected individuals presenting with hypokalaemia and unusual food cravings. METHODS: The affected individuals and two unaffected first degree relatives were enrolled into the study. Phenotypes were evaluated through history, physical examination and biochemical analysis of blood and urine. Mutation screening was performed by sequencing of SLC12A3, and determining the allele frequencies of the sequence variants found in this family in 117 ethnically matched controls. RESULTS: The index patient, her sister, father and two aunts had a history of severe salt cravings, fatigue and tetanic episodes, leading to consumption of large quantities of salt and vinegar. All affected individuals demonstrated hypokalaemia with renal potassium wasting. Genetic analysis revealed that the pseudo-dominant pattern of inheritance was due to compound heterozygosity with two novel mutations: a S546G substitution in exon 13, and insertion of AGCCCC at c.1930 in exon 16. These variants were present in the five affected individuals, but only one variant each in the unaffected family members. Neither variant was found in any of the controls. CONCLUSIONS: The diagnosis of GS was established in five members of a South African family through clinical assessment, biochemical analysis and mutation screening of the SLC12A3 gene, which identified two novel putative pathogenic mutations.


Asunto(s)
Ansia , Síndrome de Gitelman/diagnóstico , Hipopotasemia/etiología , Adulto , Anciano , Alcalosis/etiología , Calcio/orina , Familia , Femenino , Pruebas Genéticas , Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/genética , Síndrome de Gitelman/fisiopatología , Haplotipos , Heterocigoto , Humanos , Magnesio/sangre , Masculino , Mutación , Linaje , Fenotipo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Sudáfrica , Desequilibrio Hidroelectrolítico/sangre , Desequilibrio Hidroelectrolítico/etiología
16.
Genet Med ; 18(2): 180-8, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25880437

RESUMEN

PURPOSE: Phenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features. METHODS: A total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined. RESULTS: Patients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease. CONCLUSIONS: This study clarified the clinical differences between BS, GS, and p-BS/GS for the first time, which will help clinicians establish differential diagnoses for these three conditions.


Asunto(s)
Síndrome de Bartter/diagnóstico , Síndrome de Gitelman/diagnóstico , Adolescente , Adulto , Síndrome de Bartter/genética , Síndrome de Bartter/fisiopatología , Preescolar , Cloruros/orina , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Síndrome de Gitelman/genética , Síndrome de Gitelman/fisiopatología , Humanos , Laxativos/efectos adversos , Masculino , Sodio/orina
17.
Hum Mol Genet ; 24(16): 4545-58, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-25994507

RESUMEN

The STE20/SPS1-related proline/alanine-rich kinase (SPAK) controls blood pressure (BP) by phosphorylating and stimulating the Na-Cl (NCC) and Na-K-2Cl (NKCC2) co-transporters, which regulate salt reabsorption in the kidney. SPAK possesses a conserved carboxy-terminal (CCT) domain, which recognises RFXV/I motifs present in its upstream activator [isoforms of the With-No-lysine (K) kinases (WNKs)] as well as its substrates (NCC and NKCC2). To define the physiological importance of the CCT domain, we generated knock-in mice in which the critical CCT domain Leu502 residue required for high affinity recognition of the RFXI/V motif was mutated to Alanine. The SPAK CCT domain defective knock-in animals are viable, and the Leu502Ala mutation abolished co-immunoprecipitation of SPAK with WNK1, NCC and NKCC2. The CCT domain defective animals displayed markedly reduced SPAK activity and phosphorylation of NCC and NKCC2 co-transporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in mRNA levels. The SPAK CCT domain knock-in mice showed typical features of Gitelman Syndrome with mild hypokalaemia, hypomagnesaemia, hypocalciuria and displayed salt wasting on switching to a low-Na diet. These observations establish that the CCT domain plays a crucial role in controlling SPAK activity and BP. Our results indicate that CCT domain inhibitors would be effective at reducing BP by lowering phosphorylation as well as expression of NCC and NKCC2.


Asunto(s)
Presión Sanguínea , Síndrome de Gitelman/metabolismo , Mutación Missense , Proteínas Serina-Treonina Quinasas/metabolismo , Sustitución de Aminoácidos , Animales , Síndrome de Gitelman/genética , Síndrome de Gitelman/fisiopatología , Células HEK293 , Humanos , Ratones , Ratones Mutantes , Fosforilación/genética , Proteínas Serina-Treonina Quinasas/genética , Estructura Terciaria de Proteína , Miembro 3 de la Familia de Transportadores de Soluto 12/biosíntesis , Miembro 3 de la Familia de Transportadores de Soluto 12/genética
18.
J Clin Invest ; 125(5): 1793-5, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25893597

RESUMEN

Diuretics are commonly used to treat hypertension and extracellular fluid volume expansion. However, the development of compensatory responses in the kidney limits the benefit of this class of drugs. In this issue of the JCI, Grimm and colleagues use a systems biology approach in mice lacking the kinase SPAK and unravel a complex mechanism that explains thiazide diuretic resistance. The overall process involves interactions among six different cell types in the kidney.


Asunto(s)
Presión Sanguínea/fisiología , Cloruros/orina , Síndrome de Gitelman/fisiopatología , Natriuresis/fisiología , Nefronas/metabolismo , Reabsorción Renal/fisiología , Animales , Masculino
19.
J Clin Invest ; 125(5): 2136-50, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25893600

RESUMEN

Thiazide diuretics are used to treat hypertension; however, compensatory processes in the kidney can limit antihypertensive responses to this class of drugs. Here, we evaluated compensatory pathways in SPAK kinase-deficient mice, which are unable to activate the thiazide-sensitive sodium chloride cotransporter NCC (encoded by Slc12a3). Global transcriptional profiling, combined with biochemical, cell biological, and physiological phenotyping, identified the gene expression signature of the response and revealed how it establishes an adaptive physiology. Salt reabsorption pathways were created by the coordinate induction of a multigene transport system, involving solute carriers (encoded by Slc26a4, Slc4a8, and Slc4a9), carbonic anhydrase isoforms, and V-type H⁺-ATPase subunits in pendrin-positive intercalated cells (PP-ICs) and ENaC subunits in principal cells (PCs). A distal nephron remodeling process and induction of jagged 1/NOTCH signaling, which expands the cortical connecting tubule with PCs and replaces acid-secreting α-ICs with PP-ICs, were partly responsible for the compensation. Salt reabsorption was also activated by induction of an α-ketoglutarate (α-KG) paracrine signaling system. Coordinate regulation of a multigene α-KG synthesis and transport pathway resulted in α-KG secretion into pro-urine, as the α-KG-activated GPCR (Oxgr1) increased on the PP-IC apical surface, allowing paracrine delivery of α-KG to stimulate salt transport. Identification of the integrated compensatory NaCl reabsorption mechanisms provides insight into thiazide diuretic efficacy.


Asunto(s)
Presión Sanguínea/fisiología , Cloruros/orina , Síndrome de Gitelman/fisiopatología , Natriuresis/fisiología , Nefronas/metabolismo , Reabsorción Renal/fisiología , Amilorida/análogos & derivados , Amilorida/farmacología , Amoníaco/metabolismo , Animales , Transporte Biológico , Anhidrasas Carbónicas/genética , Anhidrasas Carbónicas/fisiología , Modelos Animales de Enfermedad , Activación Enzimática , Canales Epiteliales de Sodio/fisiología , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Síndrome de Gitelman/genética , Ácidos Cetoglutáricos/metabolismo , Glomérulos Renales/metabolismo , Masculino , Ratones , Ratones Noqueados , Natriuresis/genética , Comunicación Paracrina , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores Notch/fisiología , Receptores Purinérgicos P2/fisiología , Transducción de Señal , Cloruro de Sodio/farmacocinética , Simportadores de Cloruro de Sodio-Potasio/genética , Simportadores de Cloruro de Sodio-Potasio/fisiología , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo
20.
World J Pediatr ; 11(2): 113-25, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25754753

RESUMEN

BACKGROUND: In the last two decades, progress in cytogenetic and genome research has enabled investigators to unravel the underlying molecular mechanisms of inherited tubulopathies such as Bartter's and Gitelman's syndromes and helped physicians to better understand not only these two pathologic entities but also renal pathophysiology and salt sensitive hypertension. DATA SOURCES: Articles collected from PubMed and open access journals included original articles, research articles, and comprehensive reviews. They were evaluated by the authors with an special emphasis on originality and up to date information about molecular pathophysiology. RESULTS: Bartter's and Gitelman's syndromes are two different inherited salt loosing tubulopathies. They are characterized by various inability of distal nephron to reabsorb sodium chloride with resultant extarcellular volume contraction and increased activity of the renin angiotensin aldosterone system. Hypokalemic metabolic alkalosis is a common feature of these two forms of tubulopathies. Hypercalciuria characterizes the majority of Bartter's syndrome, and hypomagnesemia with hypocalciuria characterizes Gitelman's syndrome. Low blood pressure is a common feature among patients who suffered from these tubulopathies. Bartter's syndromes encompass a heterogeneous group of ion channels defects localized at the thick ascending limp of Henle's loop with resultant loss of function of sodium-potassium-2 chloride cotransporter. These defects result in the impairment of the countercurrent multiplication system of the kidney as well as calcium, potassium and acid base disturbances which in the majority of cases are proved lethal especially in the antenatal and/or immediate postnatal life period. The underlying pathology in Gitelman's syndrome is defined to the distal convoluted tubule and is related to loss of function of the sodium-chloride cotransporter. The results of this defect encompass the inability of extracellular volume homeostasis, magnesium and potassium conservation, and acid base disturbances which are generally mild and in the majority of cases are not life-threatening. CONCLUSIONS: Recent advances in molecular pathophysiology of Bartter's and Gitelman's syndromes have helped physicians to better understand the underlying mechanisms of these pathologic entities which remain obscure. Data collected from experiments among genetically manipulated animals enable us to better understand the pathophysiology of mammalian kidney and the underlying mechanisms of salt sensitive hypertension and to lay a foundation for the future development of new drugs, especially diuretics and antihypertensive drugs.


Asunto(s)
Síndrome de Bartter/fisiopatología , Síndrome de Gitelman/fisiopatología , Síndrome de Bartter/epidemiología , Síndrome de Bartter/genética , Síndrome de Gitelman/epidemiología , Síndrome de Gitelman/genética , Humanos , Incidencia , Transporte Iónico , Mutación
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