WNK1, a Gene within a Novel Blood Pressure Control Pathway, Tissue-Specifically Generates Radically Different Isoforms with and without a Kinase Domain

Abstract

ABSTRACT. WNK1 is a member of a novel serine/threonine kinase family, With-No-K, (lysine). Intronic deletions in the encoding gene cause Gordon syndrome, an autosomal dominant, hypertensive, hyperkalemic disorder particularly responsive to thiazide diuretics, a first-line treatment in essential hypertension. To elucidate the novel WNK1 BP control pathway active in distal nephron, WNK1 expression in mouse was studied. It was found that WNK1 is highly expressed in testis > heart, lung, kidney, placenta > skeletal muscle, brain, and widely at low levels. Several WNK1 transcript classes are demonstrated, showing tissue-, developmental-, and nephron-segment–specific expression. Importantly, in kidney, the most prominent transcripts are smaller than elsewhere, having the first four exons replaced by an alternative 5′-exon, deleting the kinase domain, and showing strong distal nephron expression, whereas larger transcripts show low-level widespread distribution. Alternative splicing of exons 11 and 12 is prominent—for example, transcripts containing exon 11 are abundant in neural tissues, testis, and secondary renal transcripts but are predominantly absent in placenta. The transcriptional diversity generated by these events would produce proteins greatly differing in both structure and function. These findings help further define and clarify the role of WNK1 and the thiazide-responsive pathway relevant to essential hypertension in which it participates. E-mail: Roger.Brown@ed.ac.uk