Published Online
on October 27, 2008

A more recent version of this article appeared on December 1, 2008

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Submitted on August 6, 2008
Revised on August 22, 2008

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; and 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.

^* To whom correspondence should be addressed. E-mail: juliette.hadchouel{at}college-de-france.fr.

Abstract—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

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