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A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity.

Zhang Y, Li H, Zhou J, Wang A, Yang J, Wang C, Liu M, Zhou T, Zhu L, Zhang Y, Dong N, Wu Q - Sci Rep (2014)

Bottom Line: Corin is a membrane-bound protease that regulates blood pressure by activating the natriuretic peptides.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).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.

View Article: PubMed Central - PubMed

Affiliation: Cyrus Tang Hematology Center, MOE Engineering Center of Hematological Disease, MOH Key Lab of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.

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.

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Subcellular distribution of corin proteins.(A) HEK293 cells expressing WT and the insA variant were stained for corin (green) and TGN46, a Golgi marker (red). (B) HEK293 cells expressing WT and the insA variant were stained for corin (red) and PDI, an ER marker (green). In both experiments, cell nuclei were stained with DAPI (blue) and vector-transfected cells were used as a negative control. Bar: 5 μm.
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f5: Subcellular distribution of corin proteins.(A) HEK293 cells expressing WT and the insA variant were stained for corin (green) and TGN46, a Golgi marker (red). (B) HEK293 cells expressing WT and the insA variant were stained for corin (red) and PDI, an ER marker (green). In both experiments, cell nuclei were stained with DAPI (blue) and vector-transfected cells were used as a negative control. Bar: 5 μm.

Mentions: We next examined the intracellular distribution of the variant by immunostaining. In HEK293 cells expressing WT, predominant corin staining was on the cell surface (Fig. 5A). Such staining was absent in vector-transfected cells. In cells expressing the insA variant, corin staining was more prominent intracellularly. By co-staining with TGN46, a Golgi marker, a significant portion of the insA variant was found in the Golgi (Fig. 5A). In parallel experiments of co-staining with PDI, an ER marker, no significant staining of WT or the variant was found in the ER (Fig. 5B). The data indicate that the insA variant was less efficient in trafficking through the Golgi network.


A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity.

Zhang Y, Li H, Zhou J, Wang A, Yang J, Wang C, Liu M, Zhou T, Zhu L, Zhang Y, Dong N, Wu Q - Sci Rep (2014)

Subcellular distribution of corin proteins.(A) HEK293 cells expressing WT and the insA variant were stained for corin (green) and TGN46, a Golgi marker (red). (B) HEK293 cells expressing WT and the insA variant were stained for corin (red) and PDI, an ER marker (green). In both experiments, cell nuclei were stained with DAPI (blue) and vector-transfected cells were used as a negative control. Bar: 5 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260221&req=5

f5: Subcellular distribution of corin proteins.(A) HEK293 cells expressing WT and the insA variant were stained for corin (green) and TGN46, a Golgi marker (red). (B) HEK293 cells expressing WT and the insA variant were stained for corin (red) and PDI, an ER marker (green). In both experiments, cell nuclei were stained with DAPI (blue) and vector-transfected cells were used as a negative control. Bar: 5 μm.
Mentions: We next examined the intracellular distribution of the variant by immunostaining. In HEK293 cells expressing WT, predominant corin staining was on the cell surface (Fig. 5A). Such staining was absent in vector-transfected cells. In cells expressing the insA variant, corin staining was more prominent intracellularly. By co-staining with TGN46, a Golgi marker, a significant portion of the insA variant was found in the Golgi (Fig. 5A). In parallel experiments of co-staining with PDI, an ER marker, no significant staining of WT or the variant was found in the ER (Fig. 5B). The data indicate that the insA variant was less efficient in trafficking through the Golgi network.

Bottom Line: Corin is a membrane-bound protease that regulates blood pressure by activating the natriuretic peptides.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).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.

View Article: PubMed Central - PubMed

Affiliation: Cyrus Tang Hematology Center, MOE Engineering Center of Hematological Disease, MOH Key Lab of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.

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.

Show MeSH
Related in: MedlinePlus