2 POINT MUTATIONS WITHIN THE ADDUCIN GENES ARE INVOLVED IN BLOOD-PRESSURE VARIATION

The Milan hypertensive strain of rats (MHS) develops a genetic form of renal hypertension that, when compared to its normotensive control (M NS), shows renal dysfunction similar to that of a subset of human pati ents with primary hypertension. MHS and MNS were shown to be homozygou s by multilocus minisatellite analysis and monolocus microsatellite ma rkers. We show here that one point mutation in each of two genes codin g for the membrane skeleton protein adducin is associated with blood p ressure in the Milan strain of rats. Adducin is a heterodimer formed b y alpha and beta subunits that promotes the assembly of actin with spe ctrin. MHS and MNS differ, respectively, by the amino acids Y and F at position 316 of the alpha subunit. In the beta-adducin locus, MHS is always homozygous for R at position 529 while in MNS either R or Q occ urs in that position. The R/Q heterozygotes showed lower blood pressur e than any of the homozygotes. In vitro phosphorylation studies sugges t that both of these amino acid substitutions occur within protein kin ase recognition sites. Analysis of an F-2 generation demonstrated that Y alleles segregated with a significant increment in blood pressure. This effect is modulated by the presence of the R allele of the beta s ubunit. Taken together, these findings strongly support a role for add ucin polymorphisms in causing variation of blood pressure in the Milan strain of rats.