New TMAu pubmed paper from HBRI

published 2009 Feb 27

Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria

Motika MS, Zhang J, Zheng X, Riedler K, Cashman JR.
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA.

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 17year 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.

http://www.ncbi.nlm.nih.gov/pubmed/19321370

Comment:
This is a new paper on FMO3 genetics in relation to trimethylaminuria, by the staff at the HBRI genetics lab in San Diego, one of the few labs in the world known to be researching FMO3 genes, amongst other genes. It's not clear the reason for the study (2 case studies). The words in bold are to emphasise possible important points.

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related links:
HBRI staff
HBRI page on trimethylaminuria and testing through HBRI (both DNA and urine)
Volunteer table of known FMO3 mutants, run by Dr Shephard in London
Videos on basics of genetics