Bartter Syndrome (BS) is a group of distal tubular disorders characterized by secondary hyperaldosteronism, hypokalemia, alkalosis and low-normal blood pressure. The primary defect of the BS consists of a sodium chloride loss in the thick ascending limb (TALH). Type 5 BS has been recently defined as a BS due the inhibition sodium-chloride- potassium cotransport (NKCC2) in the TALH caused by the most activating mutations of the calcium-sensing receptor gene (CaSR). It has been hypothesized that these mutations amplify the inhibitory effect of the CaSR on NKCC2 that is exerted by phospholipase A2 activation and 20-hydroxyeicosatetraenoic acid production. We described two monozygotic twin sisters with autosomal dominant hypocalcemia (ADH), due to a nonconservative activating CaSR mutation in the extracellular domain (K29E). They developed a Bartter-like syndrome with a slight phenotype. Hypokalemia occurred only at the age of 22 years in both twins and was corrected with small doses of oral potassium in one twin, while the other twin needed no potassium supplements to maintain borderline levels of plasma potassium; alkalosis was absent; plasma renin and aldosterone production was not markedly activated. In addition, the natriuretic response to furosemide, an inhibitor of NKCC2, was conserved in both twins. The K29E mutation was previously reported to produce a very marked gain-of-function of CaSR in renal HEK-293 cells transfected for the CaSR gene. The known CaSR mutations associated with type 5 BS showed a CaSR activity comparable with that of K29E mutation. CaSR mutations in patients with ADH but not BS were shown to be less activating. These findings confirm that type 5 BS is caused by CaSR mutation resulting in a conspicuous gain-of-function of CaSR. However, findings in our twins suggest that type 5 BS may manifest with different degree of severity, not related with the in vitro potency of CaSR mutations. Additional causes have to be explored to explain type 5 BS.
|Titolo:||Type 5 Bartter syndrome : a crossroad among alterations of calcium and sodium metabolism|
SOLDATI, LAURA (Penultimo)
|Settore Scientifico Disciplinare:||Settore MED/14 - Nefrologia|
|Data di pubblicazione:||2007|
|Digital Object Identifier (DOI):||10.1007/s00223-007-9057-6|
|Appare nelle tipologie:||01 - Articolo su periodico|