Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication

被引:168
作者
Treacy, EP
Akerman, BR
Chow, LML
Youil, R
Bibeau, C
Lin, J
Bruce, AG
Knight, M
Danks, DM
Cashman, JR
Forrest, SM
机构
[1] McGill Univ, Montreal Childrens Hosp, Res Inst, Montreal, PQ H3H 1P3, Canada
[2] Merck Res Labs, W Point, PA USA
[3] Seattle Biomed Res Inst, Seattle, WA 98109 USA
[4] Royal Childrens Hosp, Murdoch Inst, Melbourne, Vic, Australia
关键词
D O I
10.1093/hmg/7.5.839
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Individuals with the recessive condition trimethylaminuria exhibit variation in metabolic detoxication of xenobiotics by hepatic flavin-containing monooxygenases. We show here that mutations in the human flavin-containing monooxygenase isoform 3 gene (FMO3) impair N-oxygenation of xenobiotics and are responsible for the trimethylaminuria phenotype. Three disease-causing mutations in nine Australian-born probands have been identified which share a particular polymorphic haplotype. Nonsense and missense mutations are associated with a severe phenotype and are also implicated in impaired metabolism of other nitrogen-and sulfur-containing substrates including biogenic amines, both clinically and when mutated proteins expressed from cDNA are studied in vitro. These findings illustrate the critical role played by human FMO3 in the metabolism of xenobiotic substrates and endogenous amines.
引用
收藏
页码:839 / 845
页数:7
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