FMO3 – Trimethylaminuria

Trimethylaminuria (TMAU) is an autosomal recessive metabolic disorder characterized by deficient N-oxygenation of dietary trimethylamine leading to a fish-like body odour. The flavin-containing monooxygenase 3 (FMO3) enzyme catalyses this oxidation, and biallelic pathogenic variants in FMO3 underlie the disease. Diagnosis relies on biochemical phenotyping (urinary TMA:TMAO ratio) and genetic testing for FMO3 variants. Early identification enables targeted management such as dietary restrictions and riboflavin supplementation.

Genetic evidence for FMO3 involvement includes over 100 probands harboring diverse variant classes—missense, nonsense, frameshift, and splice site mutations. For instance, three distinct missense substitutions (M66I, R492W, P153L) were identified in a cohort of nine unrelated Australian probands (PMID:9536088). In a Korean pediatric case, compound heterozygosity for c.1091C>G (p.Ser364Ter) and c.172G>A (p.Val58Ile) segregated with TMAU (PMID:28392825). These variants account for severe enzyme deficiency and odor phenotype.

Segregation studies in multi-generation families further support pathogenicity. In two siblings homozygous for P153L, the variant leads to complete loss of FMO3 activity (PMID:10215790). A Norwegian kindred with a novel R238Q mutation showed autosomal recessive inheritance; the proband, her mother, and a great-uncle were all affected, confirming segregation with catalytic inactivity (PMID:19577495).

Functional assays of recombinant FMO3 variants demonstrate loss or severe reduction of N-oxygenation capacity. The Met82Thr and Glu32Lys substitutions abolish catalytic activity in baculovirus and bacterial expression systems (PMID:10898113, PMID:12893987). Common polymorphisms E158K and E308G exert only minor effects on activity, reinforcing that rare deleterious alleles drive TMAU pathogenesis.

Common variants such as Glu158Lys (rs2266780) and Glu308Gly occur at appreciable allele frequencies but are not sufficient to cause TMAU in isolation, as shown by unaffected carriers with normal TMAO formation (PMID:9282831). These findings underscore the necessity of two loss-of-function alleles for clinical phenotype.

In summary, definitive genetic and functional evidence establishes FMO3 as the causal gene for Trimethylaminuria. Genotyping of FMO3 is clinically valuable for diagnosis, genetic counselling, and guiding interventions to ameliorate odour and psychosocial impact. Key take-home: FMO3 mutation screening enables precise confirmation of TMAU and informs management strategies.

References

• Human molecular genetics • 1998 • Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. PMID:9536088
• The British journal of dermatology • 1999 • Sequence variations in the flavin-containing mono-oxygenase 3 gene (FMO3) in fish odour syndrome. PMID:10215790
• Pharmacogenetics • 2003 • Deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene causing trimethylaminuria. PMID:12893987
• Molecular genetics and metabolism • 2009 • A novel mutation in the flavin-containing monooxygenase 3 gene (FMO3) of a Norwegian family causes trimethylaminuria. PMID:19577495
• Chemical research in toxicology • 1997 • Human flavin-containing monooxygenase form 3: cDNA expression of the enzymes containing amino acid substitutions observed in individuals with trimethylaminuria. PMID:9282831

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