RESUMEN
INTRODUCTION: Gitelman syndrome (GS) is a rare renal tubular salt-wasting disorder. Besides kidney electrolyte loss, proteinuria and renal dysfunction were also observed. However, their incidence, risk factors, pathological features, and prognosis were unclear. METHODS: We retrospectively reviewed 116 GS patients and analyzed their clinical, genetic, and pathological characteristics. We also systematically reviewed articles on GS with proteinuria and renal dysfunction. RESULTS: Twenty-three GS patients had proteinuria (69.6%) and renal dysfunction (43.5%) with a mean age of 35.3 ± 13.2 years, and 65.2% were male. Compared to patients without proteinuria or renal dysfunction, these patients had elevated plasma angiotensin II level (440.2 ± 351.7 vs. 253.2 ± 187.4 pg/mL, p = 0.031) and three times higher incidence of diabetes. The renal pathology of nine biopsied patients indicated hypertrophy of the juxtaglomerular apparatus (100%), chronic tubulointerstitial changes (66.7%), intrarenal vascular changes (66.7%), and glomerulopathy (55.6%). More extensive renin staining was observed in patients with GS than in the control group with glomerular minor lesion (p < 0.001). During a median of 85 months (range, 11-205 months) of follow-up for 19 out of the 23 GS-renal patients, the renal function was generally stable, except one died of cancer and one developed end-stage renal disease because of concomitant membranous nephropathy and IgA nephropathy. CONCLUSION: Proteinuria and renal dysfunction were more common than expected and might indicate glomerulopathy and vascular lesions besides a tubulointerstitial injury in GS. Renal function may maintain stable with effective therapy in most cases.
Asunto(s)
Síndrome de Gitelman , Glomerulonefritis por IGA , Humanos , Masculino , Adulto Joven , Adulto , Persona de Mediana Edad , Femenino , Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/patología , Estudios Retrospectivos , Riñón/patología , Proteinuria/complicaciones , Glomerulonefritis por IGA/complicacionesRESUMEN
BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3 , which encodes the Na + -Cl - cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield. METHODS: Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants. RESULTS: A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C>T variant and intronic candidate variants demonstrated aberrant splicing patterns. CONCLUSION: Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome.
Asunto(s)
Síndrome de Gitelman , Humanos , Síndrome de Gitelman/genética , Síndrome de Gitelman/patología , Intrones/genética , Mutación , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , ExonesRESUMEN
The dysfunction of Na+-Cl- cotransporter (NCC) caused by mutations in solute carrier family12, member 3 gene (SLC12A3) primarily causes Gitelman syndrome (GS). In identifying the pathogenicity of R158Q and G212S variants of SLC12A3, we evaluated the pathogenicity by bioinformatic, expression, and localization analysis of two variants from a patient in our cohort. The prediction of mutant protein showed that p.R158Q and p.G212S could alter protein's three-dimensional structure. Western blot showed a decrease of mutant Ncc. Immunofluorescence of the two mutations revealed a diffuse positive staining below the plasma membrane. Meanwhile, we conducted a compound heterozygous model-Ncc R156Q/G210S mice corresponding to human NCC R158Q/G212S. NccR156Q/G210S mice clearly exhibited typical GS features, including hypokalemia, hypomagnesemia, and increased fractional excretion of K+ and Mg2+ with a normal blood pressure level, which made NccR156Q/G210S mice an optimal mouse model for further study of GS. A dramatic decrease and abnormal localization of the mutant Ncc in distal convoluted tubules contributed to the phenotype. The hydrochlorothiazide test showed a loss of function of mutant Ncc in NccR156Q/G210S mice. These findings indicated that R158Q and G212S variants of SLC12A3 were pathogenic variants of GS.
Asunto(s)
Síndrome de Gitelman , Hipopotasemia , Humanos , Animales , Ratones , Síndrome de Gitelman/genética , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/patología , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Hipopotasemia/genética , Mutación , FenotipoRESUMEN
BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
Asunto(s)
ADN Mitocondrial/genética , Síndrome de Gitelman/genética , Mutación , Adolescente , Adulto , Anciano , Secuencia de Bases , Niño , Preescolar , Femenino , Genotipo , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/patología , Células HEK293 , Humanos , Lactante , Riñón/metabolismo , Riñón/ultraestructura , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Modelos Biológicos , Conformación de Ácido Nucleico , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , ARN de Transferencia de Isoleucina/química , ARN de Transferencia de Isoleucina/genética , ARN de Transferencia de Fenilalanina/química , ARN de Transferencia de Fenilalanina/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Adulto JovenRESUMEN
Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.
Asunto(s)
Síndrome de Bartter/patología , Síndrome de Gitelman/patología , Túbulos Renales Distales/patología , Asa de la Nefrona/patología , Equilibrio Hidroelectrolítico/fisiología , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Síndrome de Bartter/terapia , Electrólitos/análisis , Electrólitos/uso terapéutico , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/genética , Síndrome de Gitelman/terapia , Humanos , Hiperaldosteronismo/patología , Hipercalciuria/patología , Hipopotasemia/patología , Hiponatremia/patología , Nefrocalcinosis/patología , Defectos Congénitos del Transporte Tubular Renal/patologíaRESUMEN
Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of SLC12A3 encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto's thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried SLC12A3 compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto's Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto's thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.
Asunto(s)
Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/genética , Enfermedad de Hashimoto/complicaciones , Mutación , Linaje , Proteinuria/complicaciones , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Adulto , Femenino , Predisposición Genética a la Enfermedad/genética , Síndrome de Gitelman/patología , Enfermedad de Hashimoto/genética , Enfermedad de Hashimoto/patología , Heterocigoto , Humanos , Hipopotasemia/complicaciones , Hipopotasemia/genética , Glomérulos Renales/patología , Magnesio/metabolismo , Masculino , Mutación Missense , Fenotipo , Proteinuria/genética , Proteinuria/patología , Receptores de Droga , Simportadores del Cloruro de Sodio , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismoRESUMEN
PURPOSE: Gitelman syndrome (GS) is an autosomal recessive renal tubular disease that arises as a consequence of mutations in the SLC12A3 gene, which codes for an Na-Cl cotransporter (NCC) in distal renal tubules. This study was designed to explore the mutations associated with GS in an effort to more fully understand the molecular mechanisms governing GS. METHODS: We analyzed SLC12A3 mutations in a pedigree including a 42-year-old male with GS as well as four related family members over three generations using Sanger and next generation sequencing approaches. We additionally explored the functional ramifications of identified mutations using both Xenopus oocytes and the HEK293T cell line. RESULTS: We found that the subject with GS exhibited characteristic symptoms including sporadic thirst, fatigue, excess urination, and substantial hypokalemia and hypocalciuria, although magnesium levels were normal. Other analyzed subjects in this pedigree had normal laboratory findings and did not exhibit clear signs of GS. Sequencing analyses revealed that the GS subject exhibited a homozygous missense mutation (c.2874C > G, p.N958K) in exon 24 of SLC12A3. Both parents of this GS subject, as well as his older brother and daughter all exhibited heterozygous mutations at this same site. Functional analyses in Xenopus oocytes indicated that this mutated SLC12A3 gene encodes a protein which fails to mediate normal sodium transport, and when this mutant gene was expressed in HEK293T cells, we observed significant increases in endoplasmic reticulum (ER)-stress pathway activation. CONCLUSION: The p.N958K mutation in exon 24 of SLC12A3 can trigger GS at least in part via enhancing ER stress responses.
Asunto(s)
Estrés del Retículo Endoplásmico , Síndrome de Gitelman/patología , Homocigoto , Mutación Missense , Adulto , Femenino , Síndrome de Gitelman/etiología , Síndrome de Gitelman/metabolismo , Humanos , Masculino , Linaje , Pronóstico , Miembro 3 de la Familia de Transportadores de Soluto 12/genéticaRESUMEN
Gitelman's syndrome (GS) and Bartter's syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature's experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine's ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.
Asunto(s)
Síndrome de Bartter/genética , Infecciones por Coronavirus/tratamiento farmacológico , Síndrome de Gitelman/genética , Peptidil-Dipeptidasa A/metabolismo , Fenotipo , Neumonía Viral/tratamiento farmacológico , Enzima Convertidora de Angiotensina 2 , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Síndrome de Bartter/metabolismo , Síndrome de Bartter/patología , COVID-19 , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/patología , Humanos , Hidroxicloroquina/farmacología , Hidroxicloroquina/uso terapéutico , PandemiasRESUMEN
BACKGROUND: Loss-of-function mutations in the sodium chloride (NaCl) co-transporter (NCC) of the renal distal convoluted tubule (DCT) cause Gitelman syndrome with hypokalemic alkalosis, hypomagnesemia and hypocalciuria. Since Gitelman patients are usually diagnosed around adolescence, we tested the idea that a progressive regression of the DCT explains the late clinical onset of the syndrome. METHODS: NCC wild-type and knockout (ko) mice were studied at Days 1, 4 and 10 and 6 weeks after birth using blood plasma analysis and morphological and biochemical methods. RESULTS: Plasma aldosterone levels and renal renin messenger RNA expression were elevated in NCC ko mice during the first days of life. In contrast, plasma ion levels did not differ between genotypes at age 10 days, but a significant hypomagnesemia was observed in NCC ko mice at 6 weeks. Immunofluorescent detection of parvalbumin (an early DCT marker) revealed that the fractional cortical volume of the early DCT is similar for mice of both genotypes at Day 4, but is significantly lower at Day 10 and is almost zero at 6 weeks in NCC ko mice. The DCT atrophy correlates with a marked reduction in the abundance of the DCT-specific Mg2+ channel TRPM6 (transient receptor potential cation channel subfamily M member 6) and an increased proteolytic activation of the epithelial Na+ channel (ENaC). CONCLUSION: After an initial outgrowth, DCT development lags behind in NCC ko mice. The impaired DCT development associates at Day 1 and Day 10 with elevated renal renin and plasma aldosterone levels and activation of ENaC, respectively, suggesting that Gitelman syndrome might be present much earlier in life than is usually expected. Despite an early downregulation of TRPM6, hypomagnesemia is a rather late symptom.
Asunto(s)
Síndrome de Bartter/patología , Síndrome de Gitelman/patología , Hiperaldosteronismo/patología , Túbulos Renales Distales/patología , Magnesio/metabolismo , Simportadores del Cloruro de Sodio/fisiología , Sodio/metabolismo , Animales , Síndrome de Bartter/etiología , Síndrome de Bartter/metabolismo , Síndrome de Gitelman/etiología , Síndrome de Gitelman/metabolismo , Hiperaldosteronismo/etiología , Hiperaldosteronismo/metabolismo , Túbulos Renales Distales/metabolismo , Ratones , Ratones Noqueados , Renina/metabolismo , Canales Catiónicos TRPM/metabolismoRESUMEN
Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution.
Asunto(s)
Síndrome de Bartter/clasificación , Canales de Cloruro/genética , Síndrome de Gitelman/clasificación , Sodio/metabolismo , Síndrome de Bartter/genética , Síndrome de Bartter/patología , Canales de Cloruro/metabolismo , Síndrome de Gitelman/genética , Síndrome de Gitelman/patología , Humanos , Túbulos Renales Distales/patología , Asa de la Nefrona/patología , Mutación , Reabsorción Renal/genéticaRESUMEN
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 due to 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.
Asunto(s)
Efecto Fundador , Duplicación de Gen , Síndrome de Gitelman/genética , Heterocigoto , Niño , Preescolar , Femenino , Pruebas Genéticas , Síndrome de Gitelman/patología , Humanos , Masculino , Linaje , Fenotipo , Pronóstico , Miembro 3 de la Familia de Transportadores de Soluto 12/genéticaRESUMEN
CONTEXT: Gitelman syndrome (GS) is clinically heterogeneous. The genotype and phenotype correlation has not been well established. Though the long-term prognosis is considered to be favorable, hypokalemia is difficult to cure. OBJECTIVE: To analyze the clinical and genetic characteristics and treatment of all members of 13 GS pedigrees. METHODS: Thirteen pedigrees (86 members, 17 GS patients) were enrolled. Symptoms and management, laboratory findings, and genotype-phenotype associations among all the members were analyzed. RESULTS: The average ages at onset and diagnosis were 27.6 ± 10.2 years and 37.9 ± 11.6 years, respectively. Males were an average of 10 years younger and exhibited more profound hypokalemia than females. Eighteen mutations were detected. Two novel mutations (p.W939X, p.G212S) were predicted to be pathogenic by bioinformatic analysis. GS patients exhibited the lowest blood pressure, serum K+, Mg2+, and 24-h urinary Ca2+ levels. Although blood pressure, serum K+ and Mg2+ levels were normal in heterozygous carriers, 24-h urinary Na+ excretion was significantly increased. During follow-up, only 41.2% of patients reached a normal serum K+ level. Over 80% of patients achieved a normal Mg2+ level. Patients were taking 2-3 medications at higher doses than usual prescription to stabilize their K+ levels. Six patients were taking spironolactone simultaneously, but no significant elevation in the serum K+ level was observed. CONCLUSION: The phenotypic variability of GS and therapeutic strategies deserve further research to improve GS diagnosis and prognosis. Even heterozygous carriers exhibited increased 24-h Na+ urine excretion, which may make them more susceptible to diuretic-induced hypokalemia.
Asunto(s)
Pueblo Asiatico/genética , Síndrome de Gitelman/genética , Hipopotasemia/etiología , Mutación , Adolescente , Adulto , Niño , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Genotipo , Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/patología , Heterocigoto , Humanos , Hipopotasemia/patología , Masculino , Linaje , Fenotipo , Pronóstico , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Adulto JovenRESUMEN
PURPOSE: Aldosterone proinflammatory/profibrotic effects are mediated by the induction of mononuclear leucocytes (MNL) to express oxidative stress (OxSt)-related proteins, such as p22phox, and by the activation of RhoA/Rho kinase pathway. Gitelman's syndrome (GS), an autosomal recessive tubulopathy, is an interesting opposite model to hypertension, being characterized by hypokalemia, activation of renin-angiotensin-aldosterone system yet normo/hypotension and lack of cardiovascular-renal remodeling. We aimed to evaluate the proinflammatory/profibrotic effect of aldosterone in MNL of 6 GS patients compared with 6 healthy subjects (HS). METHODS: p22phox expression and MYPT-1 phosphorylation status, a marker of RhoA/Rho kinase pathway activation, were evaluated in MNL of GS patients and HS at baseline and after incubation with aldosterone (1 × 10-8 M) alone or with canrenone (1 × 10-6 M). RESULTS: At basal condition, p22phox expression was significantly higher in HS than in GS patients (1.02 ± 0.05 densitometric unit (du) vs 0.40 ± 0.1 du, respectively). Aldosterone significantly increased p22phox expression in HS and this effect was reversed by coincubation with canrenone (1.4 ± 0.05 du and 1.09 ± 0.03 du, respectively). No significant change was reported in GS after incubation of MNL with aldosterone and/or canrenone compared with basaline. Even MYPT-1 phosphorylation was significantly higher in HS compared with GS patients at basal condition (1.16 ± 0.1 du vs 0.69 ± 0.07, respectively). Aldosterone significantly increased MYPT-1 phosphorylation only in HS (1.37 ± 0.1 du vs 0.83 ± 0.12 du in GS). CONCLUSIONS: GS patients seem to be protected by the OxSt status induced by aldosterone and revealed in HS. This human model could provide additional clues to highlight the proinflammatory/cardiovascular remodeling effects of aldosterone.
Asunto(s)
Aldosterona/farmacología , Fibrosis/prevención & control , Síndrome de Gitelman/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Inflamación/prevención & control , Adulto , Anciano , Biomarcadores/metabolismo , Estudios de Casos y Controles , Femenino , Fibrosis/metabolismo , Estudios de Seguimiento , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/patología , Humanos , Hipertensión/metabolismo , Hipertensión/patología , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Fosfatasa de Miosina de Cadena Ligera/metabolismo , NADPH Oxidasas/metabolismo , Fosforilación , Pronóstico , Transducción de Señal , Adulto JovenRESUMEN
We present a novel case of a woman with coincident occurrence of auditory and visual hallucinations, electrolyte disturbances, chloride unresponsive alkalosis, and an eating disorder. The patient was ultimately diagnosed with Gitelman syndrome comorbid with schizophreniform disorder and avoidant restrictive food intake disorder. Eating disorders are often associated with electrolyte abnormalities which, in turn, can cause or contribute to other neuropsychiatric symptoms. At the same time, psychotic disorders can lead to food intake aversions or overconsumption of fluids with associated effects on electrolyte balance. In this case, a third factor, Gitelman syndrome, resulted in persistent hypomagnesemia with metabolic alkalosis and, while separate from her eating disorder, simultaneously reinforced the patient's strong food preferences, excessive fluid intake, and excessive movement related to her complaints of persistent joint pain.
Asunto(s)
Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Síndrome de Gitelman/diagnóstico , Deficiencia de Magnesio/etiología , Desnutrición/diagnóstico , Trastornos Psicóticos/diagnóstico , Adulto , Comorbilidad , Femenino , Síndrome de Gitelman/patología , Humanos , Estudios RetrospectivosRESUMEN
Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy characterized by hypokalemic metabolic alkalosis with hypocalciuria and hypomagnesemia. GS clinical symptoms range from mild weakness to muscular cramps, paralysis or even sudden death as a result of cardiac arrhythmia. GS is caused by loss-of-function mutations in the solute carrier family 12 member 3 (SLC12A3) gene, but molecular mechanisms underlying such a wide range of symptoms are poorly understood. Here we report cryptic exon activation in SLC12A3 intron 12 in a clinically asymptomatic GS, resulting from an intronic mutation c.1669+297 T>G that created a new acceptor splice site. The cryptic exon was sandwiched between the L3 transposon upstream and a mammalian interspersed repeat downstream, possibly contributing to inclusion of the cryptic exon in mature transcripts. The mutation was identified by targeted next-generation sequencing of candidate genes in GS patients with missing pathogenic SLC12A3 alleles. Taken together, this work illustrates the power of next-generation sequencing to identify causal mutations in intronic regions in asymptomatic individuals at risk of developing potentially fatal disease complications, improving clinical management of these cases.
Asunto(s)
Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/genética , Túbulos Renales Distales/patología , Secuencia de Bases , Preescolar , Exones/genética , Femenino , Síndrome de Gitelman/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Intrones/genética , Mutación/genética , Análisis de Secuencia de ADN , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismoRESUMEN
Gitelman syndrome is an autosomal recessive distal renal tubular disorder caused by defective sodium chloride transporters. Biochemically, it presents with hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. It is usually managed with oral potassium supplements and potassium-sparing diuretics. We report a case of a 28-year-old woman whose condition worsened during pregnancy; she became resistant to standard management after delivery of her second child. She was managed in a specialist metabolic clinic through a comprehensive approach including perseverance with oral potassium supplement, weekly intravenous potassium and magnesium infusion, correction of vitamin D level and the offering of appropriate dietary advice; this controlled the patient's symptoms and prevented repeated hospital admissions. In this case report, we illustrate a patient's presentation and diagnosis with Gitelman syndrome, discuss triggers of exacerbation, review the relevant literature in terms of differential diagnoses and provide practical advice on the management of difficult cases in a specialist clinic.
Asunto(s)
Síndrome de Gitelman/tratamiento farmacológico , Magnesio/uso terapéutico , Micronutrientes/uso terapéutico , Potasio/uso terapéutico , Complicaciones del Embarazo , Adulto , Diagnóstico Diferencial , Dieta , Femenino , Síndrome de Gitelman/sangre , Síndrome de Gitelman/patología , Hospitalización , Humanos , Hipopotasemia/tratamiento farmacológico , Hipopotasemia/etiología , Infusiones Intravenosas , Magnesio/sangre , Deficiencia de Magnesio/tratamiento farmacológico , Deficiencia de Magnesio/etiología , Micronutrientes/sangre , Micronutrientes/deficiencia , Potasio/sangre , Embarazo , Índice de Severidad de la Enfermedad , Vitamina D/sangre , Vitamina D/uso terapéutico , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/etiologíaRESUMEN
Gitelman's syndrome (GS) is caused by loss-of-function mutations in SLC12A3 and characterized by hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Long-term prognosis and the role of gene diagnosis in GS are still unclear. To investigate genotype-phenotype correlation in GS and Gitelman-like syndrome, we enrolled 34 patients who showed hypokalemic metabolic alkalosis without secondary causes. Mutation analysis of SLC12A3 and CLCNKB was performed. Thirty-one patients had mutations in SLC12A3, 5 patients in CLCNKB, and 2 patients in both genes. There was no significant difference between male and female in clinical manifestations at the time of presentation, except for early onset of symptoms in males and more profound hypokalemia in females. We identified 10 novel mutations in SLC12A3 and 4 in CLCNKB. Compared with those with CLCNKB mutations, patients with SLC12A3 mutations were characterized by more consistent hypocalciuria and hypomagnesemia. Patients with 2 mutant SLC12A3 alleles, compared with those with 1 mutant allele, did not have more severe clinical and laboratory findings except for lower plasma magnesium concentrations. Male and female patients did not differ in their requirement for electrolyte replacements. Two patients with concomitant SLC12A3 and CLCNKB mutations had early-onset severe symptoms and showed different response to treatment. Hypocalciuria and hypomagnesemia are useful markers in differentiation of GS and classical Bartter's syndrome. Gender, genotypes or the number of SLC12A3 mutant alleles cannot predict the severity of disease or response to treatment.
Asunto(s)
Canales de Cloruro/genética , Síndrome de Gitelman/genética , Adolescente , Adulto , Alelos , Síndrome de Bartter/genética , Síndrome de Bartter/patología , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Genotipo , Síndrome de Gitelman/patología , Humanos , Hipopotasemia/etiología , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Adulto JovenRESUMEN
Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. The syndrome is caused by a defective thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubules of the kidneys. Gitelman syndrome could be confused with Bartter syndrome; the main differentiating feature is the presence of low urinary calcium excretion in the former. Descriptions of neuroradiological imaging findings associated with Gitelman syndrome are very scarce in the literature and include basal ganglia calcification, idiopathic intracranial hypertension and sclerochoroidal calcification. Cauda equina syndrome-like presentation has been reported, but without any corresponding imaging findings on lumbar spine MRI. We report a 13-year-old male with Gitelman syndrome who presented with altered mental status following a fall and scalp laceration and unremarkable brain CT, followed during hospitalization by somnolence and seizures. Metabolically the patient demonstrated hypokalemia and hypomagnesemia. MRI demonstrated features of encephalopathy including predominantly right-sided cerebral hemispheric signal abnormality and cytotoxic edema, with bilateral symmetric involvement of the thalami, midbrain tegmentum and tectum and cerebellar dentate nuclei. MRI after five months obtained during a later episode of encephalopathy showed resolution of the signal abnormalities with setting in of brain atrophy and also areas of newly developed cytotoxic edema in the left thalamus, bilateral dorsal midbrain and right greater than left dentate nuclei. The described abnormalities, either recurrent or in isolation, have not previously been published in patients with Gitelman syndrome. We believe that the findings are due to alteration of respiratory chain function secondary to the metabolic derangement and hence have a similar imaging appearance as encephalopathy related to mitochondrial cytopathy or metabolic encephalopathy.
Asunto(s)
Encéfalo/patología , Síndrome de Gitelman/patología , Imagen por Resonancia Magnética , Adolescente , Electroencefalografía , Humanos , Masculino , Tomografía Computarizada por Rayos XRESUMEN
We report on a 27-year-old patient presenting with chronic hypokalaemia, inappropriate kaliuresis, hypomagnesaemia and alkalosis, associated with moderate proteinuria. Genetic analysis evidenced a homozygous mutation (p.Arg399Cys) in the SLC12A3 gene coding for the sodium-chloride cotransporter (NCC), confirming the diagnosis of Gitelman syndrome. Further genetic testing did not show any mutation in NPHS2. A renal biopsy was performed in view of the unusual association with proteinuria. Light microscopy showed hypertrophy of the juxtaglomerular apparatus and discrete mesangial thickening. In addition to possible focal segmental glomerular sclerosis lesions, electron microscopy showed extensive segments of variably thickened glomerular basement membrane (GBM), contrasting with segments of regular GBM of low range thickness, and effacement of podocyte foot processes. Of interest, alterations of the GBM were also observed in a Slc12a3 knock-out mouse model for Gitelman syndrome. These data suggest that the association between Gitelman syndrome and secondary changes of the GBM is probably not coincidental. Possible mechanisms include angiotensin II- or renin-induced podocyte lesions, as well as chronic hypokalaemia.
Asunto(s)
Síndrome de Gitelman/patología , Membrana Basal Glomerular/patología , Glomérulos Renales/patología , Podocitos/patología , Proteinuria/patología , Miembro 3 de la Familia de Transportadores de Soluto 12/fisiología , Adulto , Animales , Síndrome de Gitelman/genética , Síndrome de Gitelman/metabolismo , Membrana Basal Glomerular/metabolismo , Humanos , Hipopotasemia/complicaciones , Glomérulos Renales/metabolismo , Masculino , Ratones , Ratones Noqueados , Microscopía Electrónica , Mutación/genética , Podocitos/metabolismo , Proteinuria/metabolismoRESUMEN
Gitelman's syndrome is an autosomal recessive salt-losing tubulopathy showing hypokalemic hypomagnesemic hypocalciuria with metabolic alkalosis and hyperreninemic hyperaldosteronism. This syndrome is caused by mutations in the SLC12A3 gene that encodes sodium-chloride cotransporter expressed at the apical membrane of renal distal convoluted tubule. Symptoms and renal outcomes of Gitelman's syndrome are, in general, mild and benign, and renal insufficiency from Gitelman's syndrome associated with long-standing hypokalemia and volume depletion is extremely rare. Herein, we report a 27-year-old male patient with Gitelman's syndrome who manifested renal failure, hypokalemia, severe metabolic alkalosis and altered mentality. About one year ago, the patient had been transferred to Seoul National University Hospital, because of unsolved hypokalemia, and was diagnosed as Gitelman's syndrome by clinical features and genetic analysis of the SLC12A3 gene. The patient carries a missense mutation at one allele of SLC12A3 gene (c.781C>T, p.Arg261Cys). His mother is also heterozygous for the same mutation and she had a history of hypokalemia. On this admission, the patient had recurrent bouts of vomiting induced by psychiatric eating disorder and showed severe volume depletion with hypotension, azotemia and metabolic alkalosis. Intense hydration therapy and emergency hemodialysis transiently improved his fluid-electrolyte imbalance and renal function. However, renal dysfunction progressively deteriorated despite the medical treatment. Our findings suggest that even in Gitelman's syndrome, constant monitoring for volume status and other comorbid conditions should be employed to prevent progressive renal injury.