A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes.
A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy. The objective of this study was to test whether other types of missense mutations in the hormone-binding domain could be implicated in hypertension in Japanese. Here, we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR. We did not identify the S810L mutation in our hypertensive population, indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese. However, we identified a novel missense mutation, F826Y, in three patients in a heterozygous state, in addition to four single nucleotide polymorphisms, including one synonymous mutation (L809L). The F826Y mutation is present in the MR hormone-binding domain and might affect the ligand affinity. The F826Y mutation was also identified in 13 individuals (5 hypertensives and 8 normotensives) in a Japanese general population (n=3,655). The allele frequency was 0.00178. The frequencies of the F826Y mutation in the hypertensive population (3/942) and in the hypertensive group (5/ 1,480) and the normotensive group (8/2,175) in the general population were not significantly different, suggesting that this mutation does not greatly affect hypertension. Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity, this missense mutation may contribute, to some extent, to clinical phenotypes through its effects on MR.
Kamide
Kei
K
Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Japan. kamide@hsp.ncvc.go.jp
Yang
Jin
J
Kokubo
Yoshihiro
Y
Takiuchi
Shin
S
Miwa
Yoshikazu
Y
Horio
Takeshi
T
Tanaka
Chihiro
C
Banno
Mariko
M
Nagura
Junko
J
Okayama
Akira
A
Tomoike
Hitonobu
H
Kawano
Yuhei
Y
Miyata
Toshiyuki
T
D000368:Aged; D000595:Amino Acid Sequence; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D018161:Receptors, Mineralocorticoid / Q000737:chemistry / Q000235:genetics*
D018161:Receptors, Mineralocorticoid