Abstract
Mutations in the WNK1 gene, encoding a serine-threonine kinase of the WNK (With No lysine (K)) family, have been implicated in two rare human diseases, Familial Hyperkalemic Hypertension (FHHt) and Hereditary Sensory and Autonomic Neuropathy type 2 (HSAN2). Alternative promoters give rise to a ubiquitous isoform, L-WNK1, and a kidney-specific isoform, KS-WNK1. Several other isoforms are generated through alternative splicing of exons 9, 11 and 12 but their precise tissue distribution is not known. Two additional exons, 8b and HSN2, involved in HSAN2, are thought to be specifically expressed in the nervous system. The purpose of this study was to establish an exhaustive description of all WNK1 isoforms and to quantify their relative level of expression in a panel of human and mouse tissues and in mouse nephron segments. For the latter purpose, we developed a new methodology allowing the determination of the proportions of the different isoforms generated by alternative splicing. Our results evidenced a striking tissue-specific distribution of the different isoforms and the unexpected presence of exon HSN2 in many tissues other than the nervous system. We also found exon 26 to be alternatively spliced in human and identified two new exons, 26a and 26b, within intron 26, specifically expressed in nervous tissues both in humans and mice. WNK1 should therefore no longer be designated as a 28- but as a 32-exon gene, with 8 of them - 8b, HSN2, 9, 11, 12, 26, 26a and 26b - alternatively spliced in a tissue-specific manner. These tissue-specific isoforms must be considered when studying the different roles of this ubiquitous kinase.
Highlights
WNK1 (With No lysine (K) 1) is a serine threonine kinase of the WNK family, which comprises 4 members (WNK1 to WNK4)
Large deletions of the first intron of the WNK1 gene are implicated in Familial Hyperkaliemic Hypertension (FHHt), a rare autosomal dominant disease characterized by a dysfunction of the distal nephron [1]
A new procedure for the quantification of WNK1 isoforms The aim of our study was to define the pattern of expression of all WNK1 transcripts generated by alternative splicing and to estimate precisely how much of each isoform is present in a given tissue
Summary
WNK1 (With No lysine (K) 1) is a serine threonine kinase of the WNK family, which comprises 4 members (WNK1 to WNK4). The majority of studies conducted to date have focused on its role in the kidney [2]. WNK1 plays a major role in cardiovascular tissues both in the adult mouse, where it regulates vasoconstriction in response to a1-adrenergic receptors [4], and in the mouse embryo, where it participates in arteriovenous specification [5,6]. In vitro studies clearly implicate WNK1 in cell migration, division and differentiation [7,8], possibly through the MAP kinase pathway [8,9], and large scale sequencing studies have shown a link between somatic mutations of WNK1 and several types of cancer [10,11,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
