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Molecular and Cellular Biology, December 2003, p. 9208-9221, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9208-9221.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Multiple Promoters in the WNK1 Gene: One Controls Expression of a Kidney-Specific Kinase-Defective Isoform

Celine Delaloy, Jingyu Lu,{dagger} Anne-Marie Houot, Sandra Disse-Nicodeme, Jean-Marie Gasc, Pierre Corvol, and Xavier Jeunemaitre*

INSERM U36, College de France, 75005 Paris, France

Received 5 May 2003/ Returned for modification 17 June 2003/ Accepted 23 September 2003

WNK1 is a serine-threonine kinase, the expression of which is affected in pseudohypoaldosteronism type II, a Mendelian form of arterial hypertension. We characterized human WNK1 transcripts to determine the molecular mechanisms governing WNK1 expression. We report the presence of two promoters generating two WNK1 isoforms with a complete kinase domain. Further variations are achieved by the use of two polyadenylation sites and tissue-specific splicing. We also determined the structure of a kidney-specific isoform regulated by a third promoter and starting at a novel exon. This transcript is kinase defective and has a predominant expression in the kidney compared to the other WNK1 isoforms, with, furthermore, a highly restricted expression profile in the distal convoluted tubule. We confirmed that the ubiquitous and kidney-specific promoters are functional in several cells lines and identified core promoters and regulatory elements. In particular, a strong enhancer element upstream from the kidney-specific exon seems specific to renal epithelial cells. Thus, control of human WNK1 gene expression of kinase-active or -deficient isoforms is mediated predominantly through the use of multiple transcription initiation sites and tissue-specific regulatory elements.

* Corresponding author. Mailing address: INSERM U36, College de France, 11, place Marcelin Berthelot, 75005 Paris, France. Phone: 33 (0)1 44 27 16 55. Fax: 33 (0)1 44 27 16 91. E-mail: xavier.jeunemaitre{at}college-de-france.fr.

{dagger} Present address: Department of Medical Genetics, China Medical University, Shenyang, China.

Molecular and Cellular Biology, December 2003, p. 9208-9221, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9208-9221.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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