Deletion of WNK1 first intron results in misregulation of both isoforms in renal and extrarenal tissues.
Hypertension
; 52(6): 1149-54, 2008 Dec.
Article
en En
| MEDLINE
| ID: mdl-18955660
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.
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Base de datos:
MEDLINE
Asunto principal:
Proteínas Serina-Treonina Quinasas
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Hiperpotasemia
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Hipertensión Renal
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Riñón
Idioma:
En
Revista:
Hypertension
Año:
2008
Tipo del documento:
Article