title: 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.
authors.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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.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.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Gerontology, First Hospital of Yancheng, Yancheng, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 1] Department of Epidemiology, School of Public Health, Soochow University, Suzhou, China [2] Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Aili
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Soochow University, Suzhou, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Yang
authors.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.
authors.forename: Can
authors.initials: C
authors.lastname: Wang
authors.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.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.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.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Zhou
authors.affiliation: 1] 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 [2] Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: 1] Department of Epidemiology, School of Public Health, Soochow University, Suzhou, China [2] Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] 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 [2] Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Ningzheng
authors.initials: N
authors.lastname: Dong
authors.affiliation: 1] 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 [2] Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio [3] Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D015870:Gene Expression; D023061:Gene Order; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D012697:Serine Endopeptidases / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004792:Enzyme Precursors; C119812:CORIN protein, human; D012697:Serine Endopeptidases