MOLECULAR ANALYSIS OF HUMAN PRORENIN PROSEGMENT VARIANTS IN-VITRO ANDIN-VIVO

The aspartyl protease renin, an important modulator of blood pressure in humans, is present in the circulation not only in its active form, but also as an inactive precursor, prorenin, in which a 43-amino acid prosegment blocks access of the substrate to the active site of the en zyme, Site-directed mutagenesis of the prosegment has led to the follo wing conclusions. 1) Maintenance of the enzymatically inactive state o f prorenin requires a short peptide sequence between positions 10P and 20P (where P denotes prosegment and numbering is relative to amino te rminus) of the prosegment; and 2) there is an inverse relationship bet ween the ability of prosegment mutations to activate and their effect on the secretion of the various prorenins, suggesting that this same r egion of the prosegment plays a critical role in the biosynthesis of h uman prorenin, Since these results demonstrated that single amino acid mutations could activate human prorenin to varying degrees, mutations in this region of the renin gene could be clinically important in hum ans. To test this hypothesis, genomic screening was carried out on the corresponding region of the human renin gene (exon 2) in a cohort of patients selected for a likely familial component to their hypertensio n. While this study identified a novel polymorphism in exon 2 of the h uman renin gene, evidence was not obtained for either the presence of prosegment mutations or the association of the novel polymorphism with hypertension in the patient population studied. In conclusion, both s tructure-function studies and genetic screening suggest that mutation of the prorenin prosegment is an unlikely factor in activation of the renin-angiotensin system in humans.