title: Rare mutations in SLC12A1 and SLC12A3 protect against hypertension by reducing the activity of renal salt cotransporters.
abstract: OBJECTIVE
  Screening for variants in SLC12A1 and SLC12A3 genes, encoding the renal Na:Cl (NCC) and Na:K:2Cl (NKCC2) cotransporters, respectively, in 3125 members of the Framingham Heart Study (FHS) revealed that carrying a rare mutation in one of these genes was associated with a significant reduction in blood pressure, in the risk of arterial hypertension, and of death due to cardiovascular disease. Because near 60% of the rare mutations identified have not been related to Bartter's or Gitelman's disease, the consequence of such mutations on cotransporter activity is unknown.
  
  
  METHODS
  We used the heterologous expression system of Xenopus laevis oocytes, microinjected with wild-type or mutant NCC or NKCC2 cRNAs, to examine the effect of these inferred NCC and NKCC2 mutations on the cotransporters' functional properties. Cotransporter activity was defined as the diuretic-sensitive radioactive tracer uptake and response to known modulators was assessed.
  
  
  RESULTS
  Basal NCC activity was significantly reduced in all NCC mutants and, excluding NCC-S186F, response to WNK3, WNK4, or intracellular chloride depletion was conserved. Similarly, basal activity was reduced in six out of nine NKCC2 mutants and response to WNK3 was maintained. No effect on protein expression was seen, except for NCC-S186F, which was significantly reduced.
  
  
  CONCLUSIONS
  The rare NCC or NKCC2 mutations found in the FHS significantly reduced the basal activity of the cotransporters. This observation supports that even a small, but chronic reduction of NCC or NKCC2 function results in a lower blood pressure and decreased risk of hypertension in otherwise healthy individuals in the general population.
authors.affiliation: Molecular Physiology Unit, Instituto Nacional de Cardiología Ignacio Chávez, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México Tlalpan.
authors.forename: Rocío
authors.initials: R
authors.lastname: Acuña
authors.forename: Lilia
authors.initials: L
authors.lastname: Martínez-de-la-Maza
authors.forename: José
authors.initials: J
authors.lastname: Ponce-Coria
authors.forename: Norma
authors.initials: N
authors.lastname: Vázquez
authors.forename: Penélope
authors.initials: P
authors.lastname: Ortal-Vite
authors.forename: Diana
authors.initials: D
authors.lastname: Pacheco-Alvarez
authors.forename: Norma A
authors.initials: NA
authors.lastname: Bobadilla
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
mesh_terms: D000818:Animals; D006973:Hypertension / Q000517:prevention & control*; D009154:Mutation; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D011955:Receptors, Drug / Q000235:genetics / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D011955:Receptors, Drug; C578716:Slc12a1 protein, rat; C578876:Slc12a3 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D011494:Protein Kinases; C547645:Wnk3 protein, rat; C499025:Wnk4 protein, rat; D017346:Protein Serine-Threonine Kinases