Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population
Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population
复制标题
DOI：
10.1016/j.ymgme.2006.08.008
复制
发表时间：
2007-01-01
影响因子：
3.8
通讯作者：
Shimizu, Makiko
中科院分区：
文献类型：
--
作者：
Yamazaki, Hiroshi;Fujita, Haruka;Shimizu, Makiko
含黄素单加氧酶3 (FMO3) n-氧化三甲胺（TMA）的能力降低被认为是导致代谢紊乱的原因。本研究的目的是研究FMO3基因的个体间变异。在自报有三甲胺尿的日本志愿者中，仅显示10-20%的FMO3代谢能力的病例受试者的基因组DNA被测序。对重组FMO3蛋白进行功能分析。观察到一个新的单核苷酸替代的纯合子，导致Arg500的停止密码子。该先证A生物亲本为杂合型，TMA n -氧代谢能力为100% ~ 90%。另一个先证者B有Arg500Stop和Cys197Stop密码子。先证者B的父亲和兄弟的TMA n -氧合代谢能力通过携带编码TMA n -氧合酶降低的Arg205Cys突变体明显观察到。重组Arg500Stop FMO3 cDNA在大肠杆菌膜和一系列高度纯化的FMO3 c端不同位置的截断突变体中表达，对典型的FMO3底物没有检测到的功能活性。结果表明，FMO3基因中无义突变Arg500Stop和/或Cys197Stop等位基因纯合的个体可以产生异常的TMA n -氧合。(c) 2006爱思唯尔公司版权所有。
The reduced capacity of flavin-containing monooxygenase 3 (FMO3) to N-oxidize trimethylamine (TMA) is believed to cause a metabolic disorder. The aim of this study was to investigate the inter-individual variations of FMO3. Genomic DNA of case subjects that showed only 10-20% of FMO3 metabolic capacity among self-reported trimethylaminuria Japanese volunteers was sequenced. Functional analysis of recombinant FMO3 proteins was also performed. One homozygote for a novel single nucleotide substitution causing a stop codon at Arg500 was observed. The biological parents of this Proband A were heterozygous and showed > 90% TMA N-oxygenation metabolic capacity. Another Proband B had the Arg500Stop and Cys197Stop codons. The TMA N-oxygenation metabolic capacities of the father and brother of this Proband B were apparently observed by possessing Arg205Cys mutant that coded for decreased TMA N-oxygenase. Recombinant Arg500Stop FMO3 cDNA expressed in Escherichia coli membranes and a series of highly purified truncation mutants at different positions of the C-terminus of FMO3 showed no detectable functional activity toward typical FMO3 substrates. The results suggest that individuals homozygous for either of the nonsense mutations, Arg500Stop and/or Cys197Stop alleles, in the FMO3 gene can possess abnormal TMA N-oxygenation. (c) 2006 Elsevier Inc. All rights reserved.