Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel cDNA has been identified from human heart that encodes an unusual mosaic serine protease, designated corin. Corin has a predicted structure of a type II transmembrane protein and contains two frizzled-like cysteine-rich motifs, seven low density lipoprotein receptor repeats, a macrophage scavenger receptor-like domain, and a trypsin-like protease domain in the extracellular region. Northern analysis showed that corin mRNA was highly expressed in the human heart. In mice, corin mRNA was detected by in situ hybridization in the cardiac myocytes of the embryonic heart as early as embryonic day (E) 9.5. By E11.5-13.5, corin mRNA was most abundant in the primary atrial septum and the trabecular ventricular compartment. Expression in the heart was maintained through the adult. In addition, mouse corin mRNA was also detected in the prehypertrophic chrondrocytes in developing bones. By fluorescent in situ hybridization analysis, the human corin gene was mapped to 4p12-13 where a congenital heart disease locus, total anomalous pulmonary venous return, had been previously localized. The unique domain structure and specific embryonic expression pattern suggest that corin may have a function in cell differentiation during development. The chromosomal localization of the human corin gene makes it an attractive candidate gene for total anomalous pulmonary venous return.
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PMID:Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart. 1032 93

Corin cDNA encodes an unusual mosaic type II transmembrane serine protease, which possesses, in addition to a trypsin-like serine protease domain, two frizzled domains, eight low-density lipoprotein (LDL) receptor domains, a scavenger receptor domain, as well as an intracellular cytoplasmic domain. In in vitro experiments, recombinant human corin has recently been shown to activate pro-atrial natriuretic peptide (ANP), a cardiac hormone essential for the regulation of blood pressure. Here we report the first characterization of corin protein expression in heart tissue. We generated antibodies to two different peptides derived from unique regions of the corin polypeptide, which detected immunoreactive corin protein of approximately 125-135 kDa in lysates from human heart tissues. Immunostaining of sections of human heart showed corin expression was specifically localized to the cross striations of cardiac myocytes, with a pattern of expression consistent with an integral membrane localization. Corin was not detected in sections of skeletal or smooth muscle. Corin has been suggested to be a candidate gene for the rare congenital heart disease, total anomalous pulmonary venous return (TAPVR) as the corin gene colocalizes to the TAPVR locus on human chromosome 4. However examination of corin protein expression in TAPVR heart tissue did not show evidence of abnormal corin expression. The demonstrated corin protein expression by heart myocytes supports its proposed role as the pro-ANP convertase, and thus a potentially critical mediator of major cardiovascular diseases including hypertension and congestive heart failure.
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PMID:Localization of the mosaic transmembrane serine protease corin to heart myocytes. 1108 6

Corin is a cardiac transmembrane serine protease that regulates blood pressure by activating natriuretic peptides. Corin variants have been associated with African Americans with hypertension and heart disease. Here, we report a new mutation in exon 12 of the CORIN gene identified in a family of patients with hypertension. The mutation resulted in R539C substitution in the Fz2 (Frizzled-2) domain of the corin propeptide region. We expressed and characterized the corin R539C mutant in HEK293 cells. As determined by Western blot analysis, the R539C mutation did not alter corin expression in transfected cells but impaired corin zymogen activation. In a pro-atrial natriuretic peptide processing assay, the corin mutant had reduced activity and exhibited a dominant-negative effect on wild-type corin. In addition, the R539C mutation altered corin ectodomain shedding, producing an alternative ~75-kDa fragment that was biologically inactive. Using protease inhibitors and the catalytically inactive corin mutant S985A, we showed that the ~75-kDa fragment was generated by corin autocleavage. We constructed a series of mutants by replacing single or double Arg residues in the corin propeptide and identified Arg-530 in the Fz2 domain as the alternative autocleavage site. Our results show that the corin mutation R539C identified in hypertensive patients impairs corin zymogen activation and causes an alternative autocleavage that reduces corin activity. These data support that human CORIN gene mutations causing impaired corin activity may be an underlying mechanism in hypertension.
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PMID:Corin mutation R539C from hypertensive patients impairs zymogen activation and generates an inactive alternative ectodomain fragment. 2337 61