Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria.
Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria.
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DOI：
10.1016/j.ymgme.2009.02.006
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发表时间：
2009-06
影响因子：
3.8
通讯作者：
Cashman, John R.
中科院分区：
文献类型：
--
作者：
Motika, Meike S.;Zhang, Jun;Zheng, Xueying;Riedler, Kiersten;Cashman, John R.
关键词：
三甲氨基尿症(TMAU)通常表现为受影响的人的体味。TMAU是由于饮食衍生的三甲胺(TMA)代谢减少所致。在健康人中，95%或更多的TMA被含有黄素的单加氧酶3(FMO3，EC 1.14.13.8)转化为无味的三甲胺N氧化物(TMA N氧化物)。FMO3基因的几个单核苷酸多态(SNPs)已经被描述，并导致一种酶对TMA N-氧化的功能活性降低或丧失，从而导致TMAU。在这里，我们报告了两个新的突变，从表型和基因分型观察到两个自我报告的个体。对一名患有严重TMAU的年轻女性的FMO3基因外显子区域进行了序列分析，发现了187(V187A)、158(E158K)、308(E308G)和305(E305X)位的杂合突变。家系遗传分析表明，E158K/V187A/E308G等位基因来源于母亲，E305X来源于父亲。研究了FMO3变异体V187A和V187A/E158K对几种常见FMO3底物(即5-和8-DPT、巯基咪唑(MMI)、TMA和硫代舒林酸)的氧化作用及其热稳定性。我们的发现表明，由于FMO3中V187A/E158K突变的组合，酶活性受到严重影响，可能是TMAU的原因之一。在另一项研究中，对一名17岁女性的基因分型分析显示，一种突变导致了K415之后的框架转移，并导致了一种只有486个氨基酸残基的蛋白质变体，这与严重的TMAU有关。
The disorder trimethylaminuria (TMAu) often manifests itself in a body odor for individuals affected. TMAu is due to decreased metabolism of dietary-derived trimethylamine (TMA). In a healthy individual, 95% or more of TMA is converted by the flavin-containing monooxygenase 3 (FMO3, EC 1.14.13.8) to non-odorous trimethylamine N-oxide (TMA N-oxide). Several single nucleotide polymorphisms (SNPs) of the FMO3 gene have been described and result in an enzyme with decreased or abolished functional activity for TMA N-oxygenation thus leading to TMAu. Herein, we report two novel mutations observed from phenotyping and genotyping two self-reporting individuals. Sequence analysis of the exon regions of the FMO3 gene of a young woman with severe TMAu revealed heterozygous mutations at positions 187 (V187A), 158 (E158K), 308 (E308G), and 305 (E305X). Familial genetic analysis showed that the E158K/V187A/E308G derived from the same allele from the mother, and the E305X was derived from the father. FMO3 variants V187A and V187A/E158K were characterized for oxygenation of several common FMO3 substrates (i.e., 5- and 8-DPT, mercaptoimidazole (MMI), TMA, and sulindac sulfide) and for its thermal stability. Our findings show that with the combination of V187A/E158K mutations in FMO3, the enzyme activity is severely affected and possibly contributes to the TMAu observed. In another study, genotyping analysis of a 17 year old female revealed a mutation that caused a frame shift after K415 and resulted in a protein variant with only 486 amino acid residues that was associated with severe TMAu.
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DOI：
10.1073/pnas.0602398103
发表时间：
2006-06-27
影响因子：
11.1
作者：
Eswaramoorthy, Subramaniam;Bonanno, Jeffrey B.;Swaminathan, Subramanyam
通讯作者：
Swaminathan, Subramanyam
DOI：
10.1073/pnas.0404538101
发表时间：
2004-09-07
影响因子：
11.1
作者：
Malito, E;Alfieri, A;Mattevi, A
通讯作者：
Mattevi, A
DOI：
10.1073/pnas.0800859105
发表时间：
2008-05-06
影响因子：
11.1
作者：
Alfieri, Andrea;Malito, Enrico;Mattevi, Andrea
通讯作者：
Mattevi, Andrea
影响因子：
4.1
作者：
NAGATA, T;WILLIAMS, DE;ZIEGLER, DM
通讯作者：
ZIEGLER, DM
含有单加氧酶3（FMO3）基因的黄素的多态性不容易发生高加索人的高血压。
影响因子：
--
作者：
Dolan, C;Shields, DC;Stanton, A;O'Brien, E;Lambert, DM;O'Brien, JK;Treacy, EP
通讯作者：
Treacy, EP