Genetic Mapping of Soluble Guanylyl Cyclase Genes

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Abstract
Abstract —The nitric oxide (NO) signaling system, consisting of NO synthases, soluble guanylyl cyclase, and cGMP, plays a prominent role in salt handling and regulation of blood pressure. Soluble guanylyl cyclases are heme-containing heterodimers (α/β). The α1/β1 isoform has greater NO sensitivity than the α1/β2. It has recently been shown that expression of the β subunits is altered in the kidney of the Dahl salt-sensitive rat, ie, the β1 subunit is decreased and the β2 subunit increased. However, whether soluble guanylyl cyclase is linked to salt sensitivity is not known. In the present study, we investigated linkage of guanylyl cyclase genes to blood pressure. α1 and β1 gene loci for soluble guanylyl cyclase were mapped to rat chromosome 2, and the β2 gene locus was mapped to rat chromosome 5 using fluorescent in situ metaphase hybridization. By use of a rat radiation hybrid panel, the gene loci were then further mapped with respect to known quantitative trait locus markers of salt-sensitive hypertension in the Dahl rat on chromosomes 2 and 5. Genes for α1 and β1 were closely linked by two-point analysis to Na + ,K + -ATPase α1 isoform (LOD of 15.1 and 14.0, respectively) and calmodulin-dependent protein kinase II-δ loci (LOD of 14.3 and 12.9, respectively), which have been previously shown to flank a quantitative trait locus for blood pressure in the Dahl rat. The α1 and β1 genes were closely linked (LOD of 11.3; θ, 0.4). The β2 gene locus was closely linked to the endothelin-2 (ET-2) locus (LOD of 13.0), which has been shown to cosegregate with blood pressure. We conclude that soluble guanylyl cyclase subunit loci, ie, α1, β1, and β2, are good candidates for genes controlling salt-sensitive hypertension in the Dahl rat.