A new SLC12A3 founder mutation (p.Val647Met) in Gitelman's syndrome patients of Roma ancestry

Background: Gitelman's syndrome (GS) is an autosomal recessive disorder caused by mutations in the SLC12A3 gene. GS is characterized by hypokalaemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Most of the reported patients of Roma ancestry are homozygous for an SLC12A3 intron 9 frameshifting mutation (c.1180+1G>T). Some forms of Bartter's syndrome result from mutations in the CLNCKB gene and clinically overlap with GS. Objectives: To characterize a second SLC12A3 mutation in Roma patients negative for the intron 9 variant. Methods: SLC12A3 and CLNCKB genes were analyzed by next-generation sequencing in two Spanish and Greek gypsy patients who were negative for the intron 9 splicing mutation. Sanger sequencing was performed to confirm the putative mutations in patients and family members. Results: We identified a missense variant (p.Val647Met, c.1939G>A) in both cases, and both were homozygous for Met. This mutation was also found in three additional patients; two homozygous and one heterozygous compound with the intron 9 splicing mutation. This new SLC12A3 mutation seems to be characteristic of gipsy GS patients and was linked to the same haplotype in all cases, supporting a founder origin. All the patients showed biochemical features characteristic of GS. Conclusion: We report a second founder mutation among GS patients of Roma ethnic background. The direct screening of this mutation would facilitate the characterization of patients who are negative for the more common intron 9 +1G>T mutation

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Prevalence of Novel MAGED2 Mutations in Antenatal Bartter Syndrome

International audienceBACKGROUND AND OBJECTIVES: Mutations in the MAGED2 gene, located on the X chromosome, have been recently detected in males with a transient form of antenatal Bartter syndrome or with idiopathic polyhydramnios. The aim of this study is to analyze the proportion of the population with mutations in this gene in a French cohort of patients with antenatal Bartter syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The French cohort of patients with antenatal Bartter syndrome encompasses 171 families. Mutations in genes responsible for types 1-4 have been detected in 75% of cases. In patients without identified genetic cause (n=42), transient antenatal Bartter syndrome was reported in 12 cases. We analyzed the MAGED2 gene in the entire cohort of negative cases by Sanger sequencing and retrospectively collected clinical data regarding pregnancy as well as the postnatal outcome for positive cases. RESULTS: We detected mutations in MAGED2 in 17 patients, including the 12 with transient antenatal Bartter syndrome, from 16 families. Fifteen different mutations were detected (one whole deletion, three frameshift, three splicing, three nonsense, two inframe deletions, and three missense); 13 of these mutations had not been previously described. Interestingly, two patients are females; in one of these patients our data are consistent with selective inactivation of chromosome X explaining the severity. The phenotypic presentation in our patients was variable and less severe than that of the originally described cases. CONCLUSIONS: MAGED2 mutations explained 9% of cases of antenatal Bartter syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. Our study confirmed previously published data and showed that females can be affected. As a result, this gene must be included in the screening of the most severe clinical form of Bartter syndrome

Biological characteristics of the 67 patients.

<p>Biological characteristics of the 67 patients.</p

Urinary ammonium excretion rates after acute acid load in patients with a normal acid-base status, according to the urinary acidification defect.

<p>All urinary pH values measured within the 6 hours after the acid load are plotted against all the corresponding NH₄⁺ excretion rates (logarithmic value). Patients were classified in four subgroups according to the minimal pH value and to the maximal NH₄⁺ excretion rate obtained within this 6 hours: <b>idiopathic hypocitraturia (green):</b> min. urine pH < 5.3, max. NH₄⁺ ≥ 33 μEq/min.; <b>high U. pH, high U. NH</b>_<b>4</b> <b>(blue):</b> min. urine pH ≥ 5.3, max. NH₄⁺ ≥ 33 μEq/min.; <b>high U. pH, low U. NH</b>_<b>4</b> (<b>purpura):</b> min. urine pH ≥5.3, max. NH₄⁺ < 33 μEq/min.; <b>low U. pH, low U. NH</b>_<b>4</b> <b>(red):</b> min. urine pH < 5.3, max. NH₄⁺ < 33 μEq/min. The thick line represents the regression line and the thin lines the 95% confidence intervals of the idiopathic hypocitraturia group (reference group). The horizontal dotted line is the NH₄⁺ excretion rate cut-off set at 33 μEq/min. The vertical dotted line is the urinary pH cut-off set at 5.3.</p

Demographic and medical characteristics of the patients.

<p>Demographic and medical characteristics of the patients.</p

Demographic and biological characteristics of the 56 patients with normal baseline plasma HCO₃^- undergoing the acute acid load test.

<p>Demographic and biological characteristics of the 56 patients with normal baseline plasma HCO₃^- undergoing the acute acid load test.</p