Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat

Through the genotype/phenotype cosegregation analysis of an F₂ intercross, from the crossbreeding of stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHR), we previously identified a quantitative trait locus for stroke on rat chromosome 5 (STR2) that colocalized with the genes encoding atrial and brain natriuretic peptides (ANP and BNP) and conferred a stroke-delaying effect. To further characterize ANP and BNP as candidates for stroke, we performed additional studies. Comparative sequence analysis revealed point mutations in both the coding and regulatory regions of ANP, whereas no interstrain differences were found for BNP. In in vitro studies in COS-7 and AtT-20 cells that were performed to test the relevance of a G→A substitution at position 1125, a Gly→Ser transposition in the SHRSP pro-ANP peptide resulted in different posttranslational processing of the SHRSP ANP gene product that was also associated with higher cGMP production (P