Role of the alpha-, beta-, and gamma-subunits of epithelial sodium channel in a model of polygenic hypertension.
The pathophysiological basis of Liddle's syndrome, a rare autosomal dominant form of arterial hypertension, has been found to rest on missense mutations or truncations of the beta- and gamma-subunits of the epithelial sodium channel. The hypothesis has been advanced that molecular variants of these genes might also contribute to the common polygenic forms of hypertension. We tested this hypothesis by performing a cosegregation study in a reciprocal cross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and a Wistar-Kyoto rat (WKY-1HD) reference strain. We carried out genetic mapping and chromosomal assignment of the alpha-, beta-, and gamma-subunits of the epithelial sodium channel using both linkage analysis and fluorescent in situ hybridization techniques. We demonstrate that in the rat, the beta- and gamma-subunits, as in humans, are in close linkage; they map to rat chromosome 1 and cosegregate with systolic pressure after dietary NaCl (logarithm of the odds [LOD] score, 3.7), although the peak LOD score of 5.0 for this quantitative trait locus was detected 4.4 cM away from the beta-/gamma-subunit locus. The alpha-subunit was mapped to chromosome 4 and exhibited no linkage to blood pressure phenotype. Comparative analysis of the complete coding sequences of all three subunits in the SHRSPHD and WKY-1HD strains revealed no biologically relevant mutations. Furthermore, Northern blot comparison of mRNA levels for all three subunits in the kidney showed no differences between SHRSPHD and WKY-1HD. Our results fail to support a material contribution of the epithelial sodium channel genes to blood pressure regulation in this model of polygenic hypertension.
Kreutz
R
R
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Struk
B
B
Rubattu
S
S
Hübner
N
N
Szpirer
J
J
Szpirer
C
C
Ganten
D
D
Lindpaintner
K
K
D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004247:DNA / Q000032:analysis / Q000737:chemistry; D053503:Epithelial Sodium Channels; D005260:Female; D015870:Gene Expression; D008040:Genetic Linkage; D005838:Genotype; D006973:Hypertension / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D007668:Kidney / Q000737:chemistry; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics*
D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; D015222:Sodium Channels; D004247:DNA