title: A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes.
abstract: 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.
authors.affiliation: Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Japan. kamide@hsp.ncvc.go.jp
authors.forename: Kei
authors.initials: K
authors.lastname: Kamide
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Shin
authors.initials: S
authors.lastname: Takiuchi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Miwa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horio
authors.forename: Chihiro
authors.initials: C
authors.lastname: Tanaka
authors.forename: Mariko
authors.initials: M
authors.lastname: Banno
authors.forename: Junko
authors.initials: J
authors.lastname: Nagura
authors.forename: Akira
authors.initials: A
authors.lastname: Okayama
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: 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*
chemical_list: D018161:Receptors, Mineralocorticoid