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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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Genetic variant altering corin cytoplasmic tail.(A) CORIN gene sequencing data from a WT allele (left) and a variant allele with an insertion (right). (B) Corin domain structure. TM, transmembrane; Fz, frizzled; LDLR, LDL receptor; SR, scavenger receptor. The catalytic sites His (H), Asp (D) and Ser-985 (S) in the protease domain are shown. The activation cleavage site R801-I802 is indicated. The insertion causes frameshift, creating a down-stream stop codon (*) in the cytoplasmic tail. An alternative initiation site, Met-30, is indicated by an arrowhead.
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f1: Genetic variant altering corin cytoplasmic tail.(A) CORIN gene sequencing data from a WT allele (left) and a variant allele with an insertion (right). (B) Corin domain structure. TM, transmembrane; Fz, frizzled; LDLR, LDL receptor; SR, scavenger receptor. The catalytic sites His (H), Asp (D) and Ser-985 (S) in the protease domain are shown. The activation cleavage site R801-I802 is indicated. The insertion causes frameshift, creating a down-stream stop codon (*) in the cytoplasmic tail. An alternative initiation site, Met-30, is indicated by an arrowhead.

Mentions: We sequenced CORIN exons and intron-exon boundaries in genomic DNA samples from normal and hypertensive individuals and identified a variant allele with a single adenine insertion at nucleotide position 102 (c.102_103insA, referred to as “insA variant” hereafter) in exon 1 of the CORIN gene (Fig. 1A)1625. The insertion shifted the reading frame, creating a down-stream stop codon (Fig. 1B).


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)

Genetic variant altering corin cytoplasmic tail.(A) CORIN gene sequencing data from a WT allele (left) and a variant allele with an insertion (right). (B) Corin domain structure. TM, transmembrane; Fz, frizzled; LDLR, LDL receptor; SR, scavenger receptor. The catalytic sites His (H), Asp (D) and Ser-985 (S) in the protease domain are shown. The activation cleavage site R801-I802 is indicated. The insertion causes frameshift, creating a down-stream stop codon (*) in the cytoplasmic tail. An alternative initiation site, Met-30, is indicated by an arrowhead.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Genetic variant altering corin cytoplasmic tail.(A) CORIN gene sequencing data from a WT allele (left) and a variant allele with an insertion (right). (B) Corin domain structure. TM, transmembrane; Fz, frizzled; LDLR, LDL receptor; SR, scavenger receptor. The catalytic sites His (H), Asp (D) and Ser-985 (S) in the protease domain are shown. The activation cleavage site R801-I802 is indicated. The insertion causes frameshift, creating a down-stream stop codon (*) in the cytoplasmic tail. An alternative initiation site, Met-30, is indicated by an arrowhead.
Mentions: We sequenced CORIN exons and intron-exon boundaries in genomic DNA samples from normal and hypertensive individuals and identified a variant allele with a single adenine insertion at nucleotide position 102 (c.102_103insA, referred to as “insA variant” hereafter) in exon 1 of the CORIN gene (Fig. 1A)1625. The insertion shifted the reading frame, creating a down-stream stop codon (Fig. 1B).

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