Identification and functional analysis ofCORINvariants in hypertensive patients

Abstract

Corin is a serine protease that activates atrial natriuretic peptide (ANP). CORIN gene variants have been reported in patients with hypertension. To date, however, the prevalence of CORIN variants in hypertensive patients remains unknown. To understand the prevalence and functional significance of CORIN variants in hypertension, we sequenced CORIN exons in 300 normal and 401 hypertensive individuals in a Chinese population and identified nine nonsynonymous variants, of which eight were not characterized previously. Among them, variants c.131A > G (p.Tyr13Cys), c.376G > T (p.Asp95Tyr), c.1094T > G (p.Leu334Trp), and c.1667G > A (p.Arg525His) occurred similarly in both normal and hypertensive individuals. Variants c1139G > A (p.Arg349His), c.2689C > T (p.Pro866Ser), and c.2864C > T (p.Thr924Met) were found once each in hypertensive individuals. Variant c.1683G > T (p.Arg530Ser) occurred preferentially in hypertensive individuals [10/401 (2.5%) vs. 1/300 (0.3%) in normal individuals; P = 0.023], which was confirmed in another independent cohort [9/368 (2.44%) in hypertensive and 2/377 (0.53%) in normal individuals; P = 0.033]. In biochemical and cell-based functional studies, variants p.Arg530Ser and p.Thr924Met, but not p.Tyr13Cys, p.Asp95Tyr, p.Leu334Trp, p.Arg349His, p.Arg525His, and p.Pro866Ser, exhibited reduced pro-ANP processing activity, which was caused by endoplasmic reticulum retention and poor zymogen activation, respectively. These results indicate that genetic variants impairing corin function are not uncommon in general populations and that such variants may be an important contributing factor in hypertension.

Cardiovascular Pleiotropic Effects of Natriuretic Peptides

“…When transfected in cells, this variant of PCSK6 was unable to activate corin [34]. Similarly, genetic variants in corin gene that associate with hypertension and heart diseases were reported to impair PCSK6-mediated corin activation [35,36,37].…”

N-glycosylation in the protease domain of trypsin-like serine proteases mediates calnexin-assisted protein folding

“…In cells, corin is made as a zymogen and activated on the cell surface by proprotein convertase subtilisin/kexin-6 (PCSK6) ( Chen et al, 2015 ; 2018 ). CORIN and PCSK6 variants that impair corin cell surface expression and zymogen activation have been identified in patients with hypertensive diseases ( Chen et al, 2015 ; Cui et al, 2012 ; Dong et al, 2013 ; 2014 ; Dries et al, 2005 ; Zhang et al, 2014 ; 2017 ).…”

A conserved LDL-receptor motif regulates corin and CD320 membrane targeting in polarized renal epithelial cells

“…Corin is a type II transmembrane protein with a cytoplasmic tail and an extended extracellular region containing distinct modular structures ( Hooper et al, 2000 ; Yan et al, 2000 ). In non-polarized cardiomyocytes and human embryonic kidney (HEK) 293 cells, corin is expressed on the entire cell surface ( Gladysheva et al, 2008 ; Zhang et al, 2015 ; Zhang et al, 2017 ). In contrast, corin is localized on the apical, but not basolateral, membrane in polarized renal epithelial cells ( Dong et al, 2016 ; Polzin et al, 2010 ).…”