MAPPING AND SEQUENCE-ANALYSIS OF THE GENE ENCODING THE BETA-SUBUNIT OF THE EPITHELIAL SODIUM-CHANNEL IN EXPERIMENTAL-MODELS OF HYPERTENSION

Objective: To investigate whether mutations in the beta subunit of the epithelial sodium channel (Scnn1b) contribute to the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR) and the Dahl salt-sensitive rat. Design: We determined the chromosome location of t he rat Scnn1b gene, tested for cosegregation with blood pressure, and sequenced near full-length Scnn1b complementary DNAs (cDNAs) from SHR and Dahl salt-sensitive rats. Methods: Chromosome mapping was performe d by somatic cell hybrid analysis and by linkage analysis in recombina nt inbred strains derived from SHR and Brown-Norway rats. Cosegregatio n analysis was performed by testing for correlations between blood pre ssure and Scnn1b genotypes in these strains. DNA sequencing was perfor med on cDNAs prepared from reverse-transcribed messenger RNA derived f rom rat kidney. Results: The Scnn1b gene was closely linked to the Sa gene on rat chromosome 1. Blood pressure correlated significantly with Scnn1b gene in the recombinant inbred strains. Analysis of near full- length Scnn1b cDNAs from SHR and Dahl rats failed to reveal any coding sequence mutations that could affect the predicted amino acid sequenc e of the Scnn1b protein. Conclusion: The Scnn1b gene maps near the Sa gene in a region of rat chromosome 1 involved in the inherited control of blood pressure. If disordered activity of the epithelial cell sodi um channel contributes to the pathogenesis of hypertension in the SHR or Dahl models, it must stem from genetic lesions in sequences that re gulate Scnn1b function or in sequences important to the structure or f unction of the other sodium channel subunits.