This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 52/6/1149    most recent HYPERTENSIONAHA.108.120899v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Delaloy, C. Articles by Hadchouel, J. Search for Related Content PubMed PubMed Citation Articles by Delaloy, C. Articles by Hadchouel, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Related Collections Animal models of human disease Other hypertension

(Hypertension. 2008;52:1149.)
© 2008 American Heart Association, Inc.

Original Articles

Deletion of WNK1 First Intron Results in Misregulation of Both Isoforms in Renal and Extrarenal Tissues

Céline Delaloy; Emilie Elvira-Matelot; Maud Clemessy; Xiao-ou Zhou; Martine Imbert-Teboul; Anne-Marie Houot; Xavier Jeunemaitre; Juliette Hadchouel

From the INSERM (C.D., E.E.-M., X.Z., A.-M.H., X.J., J.H.), Unit 772; Faculté de Médecine (C.D., E.E.-M., X.Z., A.-M.H., X.J., J.H.), Université Paris Descartes Paris V; Collège de France (C.D., E.E.-M., M.C., X.Z., A.-M.H., X.J., J.H.); INSERM (M.C.), Unit 833; Université Pierre et Marie Curie Paris VI (M.I.-T.), LPGCR-Institut des Cordeliers; CNRS (M.I.-T.), UMR7134, Paris, France. Current address: Gladstone Institute of Neurological Diseases (C.D.), University of California, San Francisco.

Correspondence to Juliette Hadchouel, INSERM Unit 772, College de France, 11 Place Marcelin Berthelot, 75005 Paris, France. E-mail juliette.hadchouel{at}college-de-france.fr

Large deletions in intron 1 of the with-no-lysine kinase type 1 (WNK1) gene cause familial hyperkalemic hypertension. Alternative promoters generate functionally different isoforms: long ubiquitous isoforms (L-WNK1) and a kidney-specific isoform (KS-WNK1) lacking kinase activity. It remains unclear whether the disease-causing mutations selectively modify the synthesis of 1 or both types of isoforms. Using a transgenic mouse model, we found that intron 1 deletion resulted in the overexpression of L- and KS-WNK1 in the distal convoluted tubule and ubiquitous ectopic KS-WNK1 expression. Phylogenetic and functional analysis of the minimal 22-kb intron 1 deletion identified 1 repressor and 1 insulator, potentially preventing interactions between the regulatory elements of L-WNK1 and KS-WNK1. These results provide the first insight into the molecular mechanisms of WNK1-induced familial hyperkalemic hypertension.

Key Words: hypertension • WNK1 • FHHt • transgenic • insulator • repressor

This article has been cited by other articles:

				G. Gamba The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs Am J Physiol Renal Physiol, October 1, 2009; 297(4): F838 - F848. [Abstract] [Full Text] [PDF]