Endocrine Abstracts

The heart not only has a mechanical function of pumping blood through vessels but also acts as an endocrine gland. In its endocrine function, the heart releases atrial natriuretic peptide (ANP), a hormone of a large family of natriuretic peptides. ANP is secreted from cardiac atria as an inactive preprohormone. In post-translational modification, 25-amino acid signal sequence is cleaved from preprohormone to produce proANP of 126-amino acid, which is the major form of ANP stored in intracellular granules of atria. Following stimulation of atrial cells by increased blood pressure, proANP is released and rapidly converted to 28-amino acid C-terminal mature ANP on cell surface by cardiac transmembrane serine protease corin. ANP regulates salt-water balance and blood pressure by promoting renal sodium and water excretion and stimulating vasodilation. Among other factors, calcium dependent secretion activator (CADPS) is one of the proteins that controls ANP secretion from the heart in stressed situations. Defects in the ANP pathway contribute to major diseases such as hypertension, cardiac hypertrophy and heart failure. The present study was designed to screen hypertensive cardiovascular patients to determine possible pathogenic mutations in genes involved in the synthesis of ANP from the heart using whole exome sequencing (WES). Thirteen hypertensive cardiovascular patients from three families (3 patients in 1st, 21-48 years; 5 in 2nd, 43-72 years and 5 patients in 3rd, 19-47 years of age) were selected for WES. DNA Isolation Kit (QIAamp DNA mini-Kit) was used to extract genomic DNA at City Lab, Rawalpindi, Pakistan, which was then taken to Genome Institute of Singapore (GIS), Singapore, where final dilutions of 25μl DNA were outsourced to Proteomics Lab, Macrogen Asia Pacific, Singapore for WES. Subsequent bioinformatics analysis was performed at GIS, Singapore. We identified 3 mutations in 2 genes, CADPS and CORIN, involved in the synthesis of ANP from the heart. Two variants in CADPS gene were observed; one splicing likely pathogenic variant (c. 969+3A>G) in all patients of family 1 and other missense (c. 308A>C, p. Glu103Ala) variant of uncertain significance (VUS) was witnessed in two patients of family 2. Both variants were already reported but are extremely rare in GnomAD database. In addition, a novel splicing (c. 618-2_618-1insT) VUS was identified in CORIN gene in only one patient of family 1. In conclusion, our results identified mutations in two genes involved in the synthesis of ANP from the heart, which may cause hypertension related cardiovascular diseases.