Genetic analysis of the beta subunit of the epithelial Na+ channel in essential hypertension.
Mutations of the last exon of the beta subunit of the amiloride-sensitive epithelial Na+ channel (betaENaC) can lead to Liddle's syndrome, a rare monogenic form of hypertension. The objective of this study was to test whether more subtle changes of betaENaC could be implicated in essential hypertension. After determination of the betaENaC coding gene organization (12 exons spanning 23.5 kb), a systematic screening of the last exon of the gene was performed in 525 subjects (475 whites, 50 Afro-Caribbeans), all probands of hypertensive families. This search was extended to the remaining 11 exons in a subset of 101 probands with low-renin hypertension. Seven amino acid changes were detected: G589S, T594M, R597H, R624C, E632G (last exon), G442V, and V434M (exon 8). These genetic variants were more frequent in subjects of African origin (44%) than in whites (1%). The functional properties of the variants were analyzed in Xenopus oocytes by two independent techniques, ie, electrophysiology and 22Na+ uptake. Small but not significant differences were observed between the variants and wild type. The clinical evaluation of the family bearing the G589S variant, which provided the highest relative ENaC activity, did not show a cosegregation between the mutation and hypertension. The present study illustrates the difficulty in establishing a relation of causality between a susceptibility gene and hypertension. Furthermore, it does not favor a substantial role of the betaENaC gene in essential hypertension.
Unité INSERM U36, Collège de France and Laboratoire de Génétique Moléculaire, Hôpital Broussais, Paris, France.
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A
Persu
P
P
Barbry
F
F
Bassilana
A M
AM
Houot
R
R
Mengual
M
M
Lazdunski
P
P
Corvol
X
X
Jeunemaitre
D000328:Adult; D000818:Animals; D001483:Base Sequence; D004848:Epithelium / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis
D015222:Sodium Channels; D012964:Sodium