RESUMEN
Based on the Chinese Children Genetic Kidney Disease Database (CCGKDD), we established a pediatric Gitelman syndrome (GS) cohort to explore the phenotype and genotype characteristics. Thirty-two patients with SLC12A3 gene variants were collected. Five cases (16%) were homozygous, 16 (50%) were compound heterozygous, 10 (31%) carried only a single variant, and the other one harbored two de novo variants beyond classification. p.(T60M) was found in eight patients. The average diagnosis age was 7.79 ± 3.54 years. A total of 31% of the patients were asymptomatic. Muscle weakness was the most common symptom, accounting for 50%. Earlier age of onset (4.06 ± 1.17 yr vs. 8.10 ± 3.46 yr vs. 8.61 ± 3.56 yr, p< 0.05) and lower urinary calcium-creatinine ratio (p = 0.024) were found in the homozygous group than those in the heterozygous and compound heterozygous group. Patients with p.(T60M) variant had an earlier age of onset (4.01 ± 2.83 yr vs. 6.92 ± 3.07 yr, p = 0.025) and lower urinary calcium-creatinine ratio (p = 0.056). Thus, more than 30% of GS children have no clinical symptoms. Homozygous variant and the p.(T60M) variant may be associated with earlier onset and lower urinary calcium excretion in Chinese pediatric GS.
Asunto(s)
Pueblo Asiatico/genética , Síndrome de Gitelman/genética , Adolescente , Edad de Inicio , Calcio/orina , Niño , Preescolar , Creatinina/orina , Enanismo/genética , Femenino , Estudios de Asociación Genética , Síndrome de Gitelman/etnología , Síndrome de Gitelman/orina , Humanos , Hipopotasemia/genética , Lactante , Masculino , Debilidad Muscular/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/genéticaRESUMEN
BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessive disease caused by loss-of-function mutations in the SLC12A3 gene, and is characterized by hypokalemia and metabolic alkalosis. In this study, we aimed to study the genotype, phenotype, and treatment in 42 GS patients, the largest sample size so far in mainland China. METHOD: We retrospectively studied the clinical data and genetic characteristics of 42 patients diagnosed with GS in Peking Union Medical College Hospital from 2012 to 2015. Therapeutic efficacy of spironolactone and potassium supplements was also studied retrospectively. RESULTS: Eighty-one mutation alleles were found in 42 patients, and total of 52 distinctly different mutation alleles were identified, of which 15 were new mutation alleles. p.Asp486Asn was a hotspot in our series, with the allele frequency being 19.7 % (16/81), and was found in 13 patients (31.0 %). Treatment with spironolactone or potassium supplements alone significantly increased serum potassium concentration by 0.36 ± 0.37 and 0.45 ± 0.35 mmol/l, respectively (both P < 0.05), and combined therapy with spironolactone and potassium increased serum potassium concentration by 0.69 ± 0.64 mmol/l (P < 0.05). CONCLUSIONS: 18.5 % (15/81) mutation sites identified in 42 Chinese GS patients are novel. p.Asp486Asn mutation is a hotspot, which is different from the reports from other countries. Spironolactone could moderately elevate serum potassium level, and spironolactone in combination with potassium supplements tended to be more effective.
Asunto(s)
Suplementos Dietéticos , Diuréticos/uso terapéutico , Síndrome de Gitelman/genética , Síndrome de Gitelman/terapia , Mutación , Potasio/uso terapéutico , Espironolactona/uso terapéutico , Adolescente , Adulto , Pueblo Asiatico/genética , China , Análisis Mutacional de ADN , Suplementos Dietéticos/efectos adversos , Diuréticos/efectos adversos , Femenino , Predisposición Genética a la Enfermedad , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/etnología , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Potasio/efectos adversos , Potasio/sangre , Estudios Retrospectivos , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Espironolactona/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Gitelman's syndrome is an inherited tubular disorder characterized by sodium wasting, low blood pressure, secondary hyperaldosteronism, metabolic alkalosis, hypokalemia, hypomagnesemia of renal origin, and hypocalciuria. The majority of patients with this syndrome carry inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive Na (+)-Cl (-) cotransporter (NCC) located in the distal convoluted tubule, which is involved in renal sodium reabsorption. This suggests that the SLC12A3 gene is involved in mediation of blood pressure levels. The aim of the present study was to investigate relationships between single nucleotide polymorphisms (SNPs) in the human SLC12A3 gene and essential hypertension (EH) in Japanese. METHOD: We selected 3 SNPs in the human SLC12A3 gene (T180K, A569V, L849H), and performed a case-control study of 315 EH patients and 305 normotensive (NT) individuals. RESULTS: There was no significant difference in overall distribution of genotypes or alleles of any of the SNPs between the EH and NT groups. CONCLUSION: We conclude that the causal gene of Gitelman's syndrome is not involved in determining blood pressure levels.
Asunto(s)
Síndrome de Gitelman/genética , Hipertensión/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Droga/genética , Simportadores/genética , Adulto , Alelos , Pueblo Asiatico/genética , Presión Sanguínea/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Síndrome de Gitelman/etnología , Humanos , Hipertensión/etnología , Japón , Masculino , Persona de Mediana Edad , Miembro 3 de la Familia de Transportadores de Soluto 12Asunto(s)
Consanguinidad , Emigración e Inmigración , Enfermedades Renales/genética , Túbulos Renales , Acidosis Tubular Renal/genética , Proteína 1 de Intercambio de Anión de Eritrocito/genética , Síndrome de Bartter/genética , Niño , Claudinas/genética , Síndrome de Gitelman/etnología , Síndrome de Gitelman/genética , Humanos , Hipercalciuria/genética , Hiperoxaluria/epidemiología , Hiperoxaluria/genética , Cálculos Renales/genética , Nefrocalcinosis/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Factores de Riesgo , Romaní/genética , España/epidemiología , Cálculos Urinarios/genéticaRESUMEN
A soluble (pro)renin receptor (sPRR) circulates in plasma and is able to bind renin and prorenin. It is not known whether plasma sPRR concentrations vary with the activity of the renin-angiotensin system. We measured plasma sPRR, renin, prorenin, and aldosterone concentrations in 121 white and 9 black healthy subjects, 40 patients with diabetes mellitus, 41 hypertensive patients with or without renin-angiotensin system blockers, 9 patients with primary aldosteronism, and 10 patients with Gitelman syndrome. Median physiological plasma sPRR concentration was 23.5 ng/mL (interquartile range, 20.9-26.5) under usual uncontrolled sodium diet. sPRR concentration in healthy subjects, unlike renin and prorenin, did not display circadian variation or dependence on age, sex, posture, or hormonal status. sPRR concentrations were ≈25% lower in black than in white subjects, whereas renin concentrations were ≈40% lower. Patients with diabetes mellitus (average renin-high prorenin levels) and with hypertension only (average renin-average prorenin levels) had sPRR concentrations similar to healthy subjects. Renin-angiotensin system blockade was associated with increase of sPRR concentration by ≈12%. sPRR in patients with primary aldosteronism (low renin-low prorenin) and Gitelman syndrome (high renin-high prorenin) were similar and ≈10% higher than in healthy subjects. There was no correlation between sPRR and renin or prorenin. In conclusion, our results show that plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity.