Endocrine Abstracts

Arginine vasopressin (AVP) is a neurohormone, which regulates blood and extracellular fluid volume and hence blood pressure (BP). AVP has its chief action in kidneys where it reduces flow of urine, increases permeability of convoluted tubules of kidneys to water and its reabsorption. It binds to receptors on sweat glands and decreases water loss by perspiration from the skin. Also, AVP binds to peripheral arteriolar receptors, causing vasoconstriction and increase in BP. The synthesis of vasopressin occurs in paraventricular and supra-optic nuclei of the hypothalamus. The mRNA encoding AVP is translated into preprohormone that is delivered into endoplasmic reticulum with concomitant signal peptide removal. The resulting prohormone is folded and delivered to Golgi apparatus where the precursor is cleaved and post-translationally modified into mature hormone. The newly synthesized neurohormone is packed in granules in Golgi complex, which move down the axons, through the stalk, to the posterior pituitary, where AVP is stored and released in response to appropriate stimuli. The main physiological stimulus for release of AVP is an increase in osmotic pressure in circulating blood. AVP causes retention of water by kidneys, which reduces plasma osmolality. The transcription factor cAMP responsive element-binding protein 3 like 1 (CREB3L1) is an important component for cellular homeostasis, particularly within cell types with high peptide secretory capabilities. CREB3L1 serves an important role in body fluid homeostasis through its transcriptional control of AVP gene. In this study, hypertensive cardiovascular patients were screened using whole exome sequencing (WES) to find possible pathogenic mutations in different genes of AVP pathway. Thirteen hypertensive cardiovascular patients from three families (3 patients in 1^st from 21-48; 5 in 2^nd from 43-72 and 5 patients in 3^rd from 19-47 years of age) were selected for WES. Genomic DNA was extracted (DNA Isolation Kit from QIAamp DNA mini Kit) at Department of Biosciences, University of Wah, Wah Cantt, Rawalpindi, Pakistan. DNA obtained was 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. The results identified a novel homozygous splice region variant (1524-1A>G) in CREB3L1 gene in all patients. In addition, a novel heterozygous splice region variant (340-2_340-1insCCC) was also identified in SEC63 gene in 10/13 patients. In conclusion, we report novel mutations in two genes involved in AVP synthesis pathway in our patients with hypertensive cardiovascular diseases.