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

Mar 27, 2009Molecular genetics and metabolism

New human gene variants linked to the condition causing fishy body odor

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Abstract

Two novel mutations in the FMO3 gene were identified in individuals with severe trimethylaminuria (TMAu).

TMAu is linked to decreased metabolism of dietary-derived trimethylamine due to FMO3 enzyme mutations.
Healthy individuals convert over 95% of trimethylamine to non-odorous trimethylamine N-oxide.
Mutations V187A, E158K, E308G, and E305X in the FMO3 gene were found in a young woman with severe TMAu.
Familial analysis indicated that certain mutations were inherited from the mother and father.
The combination of V187A and E158K mutations significantly impaired enzyme activity, contributing to TMAu.
A separate mutation in a 17-year-old female resulted in a protein variant with 486 amino acids and was associated with severe TMAu.

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

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