A Corin Variant Identified in Hypertensive Patients That Alters Cytoplasmic Tail and Reduces Cell Surface Expression and Activity

Abstract

Corin is a membrane-bound protease that regulates blood pressure by activating the natriuretic peptides. CORIN variants have been associated with hypertension and heart disease in African Americans. In this study, we conducted targeted exome sequencing and identified an insertion variant, c.102_103insA, in exon 1 of the CORIN gene. Analysis of two independent cohorts showed that the variant was preferentially present in hypertensive patients (38/795 or 4.78% vs. 4/632 or 0.63% in normal individuals, p = 4.14E-6). The insertion shifted the reading frame, resulting in a corin variant with a truncated cytoplasmic tail. In cell-based studies, the corin variant exhibited poor trafficking in the Golgi, reduced cell surface expression and zymogen activation, and low natriuretic peptide processing activity. Compared with normal individuals with the wild-type allele, individuals with the variant allele had lower levels of plasma corin [0.59 ± 0.07 ng/mL (n = 25) vs. 0.91 ± 0.02 ng/mL (n = 215), p<0.001] and higher levels of plasma N-terminal pro-atrial natriuretic peptide (NT-pro-ANP) [2.39 ± 3.6 nmol/L (n = 21) vs. 0.87 ± 0.6 nmol/L (n = 48), p = 0.005]. These results indicate that the variant altered corin structure and impaired the natriuretic peptide processing activity in vivo. The results highlight corin defects as an important underlying mechanism in hypertension.

Atrial natriuretic peptide in cardiovascular biology and disease (NPPA)

“…In mice, disrupting the Corin gene abolished pro-ANP processing and caused spontaneous hypertension (Chan et al, 2005; Wang et al, 2012b), indicating that corin is the primary pro-ANP convertase in vivo . In humans, CORIN variants and mutations that impair corin activity have been identified in patients with hypertension and heart disease (Dong et al, 2013; Dries et al, 2005; Wang et al, 2012a; Wang et al, 2008; Zhang et al, 2014). …”

Localization of corin and atrial natriuretic peptide expression in human renal segments

“…In mice, corin deficiency prevents pro-ANP processing, impairs renal sodium excretion, and causes salt-sensitive hypertension and cardiac hypertrophy [9–12]. In humans, CORIN variants have been identified in hypertensive patients [13–17]. Most recently, we have identified proprotein convertase subtilisin/kexin-6 (PCSK6) as a primary corin activator [18].…”

A novel cytoplasmic tail motif regulates mouse corin expression on the cell surface

“…In transfected cells, the corin variant exhibited poor trafficking in the Golgi and low expression on the cell surface [46]. Individuals carrying this variant CORIN allele have higher levels of unprocessed natriuretic peptides in blood and are more likely to develop hypertension than individuals with the WT allele [46]. These results support the idea that the corin cytoplasmic tail is of functional importance and that genetic mutations altering corin cytoplasmic sequences may impair corin activity and contribute to hypertension.…”

“…Recently, we identified a human CORIN minor allele encoding a variant with a truncated cytoplasmic tail that lacks the DDNN motif [46]. In transfected cells, the corin variant exhibited poor trafficking in the Golgi and low expression on the cell surface [46].…”

“…Recently, we identified a human CORIN minor allele encoding a variant with a truncated cytoplasmic tail that lacks the DDNN motif [46]. In transfected cells, the corin variant exhibited poor trafficking in the Golgi and low expression on the cell surface [46]. Individuals carrying this variant CORIN allele have higher levels of unprocessed natriuretic peptides in blood and are more likely to develop hypertension than individuals with the WT allele [46].…”