Two novel mutations of the FMO3 gene in a proband with trimethylaminuria

Area of Science:

• Biochemistry
• Human Genetics
• Pharmacology

Background:

• Mammalian flavin-containing monooxygenases (FMOs) are critical enzymes involved in the N-oxygenation of various compounds, including drugs and xenobiotics.
• The FMO3 gene encodes the primary catalytically active FMO isoform in the human liver, playing a significant role in xenobiotic metabolism.
• Trimethylaminuria (TMA) is a metabolic disorder characterized by the inability to metabolize trimethylamine, leading to its accumulation.

Observation:

• Two novel missense mutations, M66I and R492W, were identified in the FMO3 gene of a patient with trimethylaminuria (TMA).
• This represents the first documented case of compound heterozygosity for rare FMO3 mutations causing TMA.
• Previously identified mutations (P153L, E305X) explained TMA in eight unrelated Australian families of British origin.

Findings:

• The identified compound heterozygous mutations (M66I and R492W) in the FMO3 gene are associated with trimethylaminuria (TMA).
• This finding expands the spectrum of known FMO3 mutations responsible for TMA.
• The study highlights the genetic heterogeneity underlying TMA.

Implications:

• The discovery of compound heterozygosity for rare FMO3 alleles broadens the understanding of genetic causes for TMA.
• This suggests that a wider range of rare FMO3 mutations may exist in populations, contributing to TMA.
• Further genetic screening for diverse FMO3 alleles is warranted for accurate TMA diagnosis and potential therapeutic strategies.