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

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

Edité par CCSD ; American Heart Association -

International audience. 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.

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