The role of Wnk4 in polygenic hypertension: a candidate gene analysis on rat chromosome 10.
Linkage analyses in experimental crosses of stroke-prone spontaneously hypertensive (SHRSP) and normotensive Wistar-Kyoto (WKY) rats have strongly suggested the presence of quantitative trait loci (QTL) influencing blood pressure and ACE levels on rat chromosome 10, which have been confirmed in multiple independent studies. Analysis of the orthologous region on human chromosome 17 also revealed significant linkage to blood pressure in several populations. Wnk4, a gene previously identified to cause pseudohypoaldosteronism type II, a rare mendelian form of arterial hypertension, is located on human chromosome 17. The hypothesis has been advanced that molecular variants of this gene might contribute to common polygenic forms of hypertension, since Wnk4 is located in a region of conserved synteny that demonstrates an overlap between quantitative trait loci for primary hypertension in humans and rats. In this report, we describe the confirmation of the blood pressure QTL on rat chromosome 10 by congenic approaches, spanning the Wnk4 locus. Comparative analysis of the complete coding sequence of Wnk4 in SHRSP and WKY strains revealed no mutation and demonstrated high conservation between rat and human proteins. Furthermore, comparison of mRNA levels in the kidney showed no differences between SHRSP and WKY. Additionally, we excluded a secondary effect of blood pressure on the transcriptional regulation of Wnk4. Our results fail to support a material contribution of Wnk4 to blood pressure regulation in this model of polygenic hypertension. Thus, Wnk4 is likely not to represent the underlying disease gene for the QTL captured in chromosome 10 congenic animals.
Monti
Jan
J
Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13092 Berlin, Germany.
Zimdahl
Heike
H
Schulz
Herbert
H
Plehm
Ralph
R
Ganten
Detlev
D
Hübner
Norbert
N
D000595:Amino Acid Sequence; D000818:Animals; D020296:Animals, Congenic; D001794:Blood Pressure / Q000235:genetics; D002875:Chromosomes; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008969:Molecular Sequence Data; D010641:Phenotype; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017386:Sequence Homology, Amino Acid
D011506:Proteins; D012333:RNA, Messenger; C499025:Wnk4 protein, rat; D017346:Protein Serine-Threonine Kinases; C433806:WNK4 protein, human