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FMO3
flavin containing dimethylaniline monoxygenase 3
The FMO3 gene provides instructions for an enzyme primarily found in the liver that processes nitrogen-containing compounds from the diet, including trimethylamine, and is involved in metabolising certain medications. FMO3 encodes a flavin-containing monooxygenase enzyme crucial for detoxifying various substances within the body.
FMO3 is located on the long (q) arm of chromosome 1, at band 1q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The FMO3 gene, or flavin containing dimethylaniline monoxygenase 3, provides instructions for creating an enzyme that is a member of the flavin-containing dimethylaniline monooxygenase (FMO) enzyme family. These enzymes are vital for breaking down compounds that contain nitrogen, sulphur, or phosphorus. The FMO3 enzyme is predominantly active in the liver and is responsible for processing nitrogen-containing compounds derived from food.
What the gene does
The FMO3 enzyme's main function is to metabolise various compounds, particularly those containing nitrogen. A key substance it processes is trimethylamine, which is produced in the intestines by bacteria digesting certain proteins found in foods like eggs, liver, legumes, and specific types of fish. Trimethylamine is known for its strong, fishy odour. The FMO3 enzyme normally converts this trimethylamine into trimethylamine-N-oxide, a compound that has no smell and is subsequently excreted from the body via urine.
Beyond dietary compounds, the FMO3 enzyme is also thought to play a role in metabolising various medications. This includes drugs such as the anti-cancer medication tamoxifen, the anti-inflammatory drug benzydamine, the antifungal ketoconazole, and certain antidepressants. Additionally, it may be involved in processing nicotine, suggesting its broad role in detoxification and drug metabolism. Variations in the FMO3 gene can influence how effectively this enzyme breaks down these substances, potentially explaining differing individual responses to certain drugs.
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Chromosome location
The FMO3 gene is located on chromosome 1, specifically at position 1q24.3. This means it resides on the long (q) arm of chromosome 1, within region 24, band 3.
Protein structure
The FMO3 gene codes for a protein that is 532 amino acids long. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the FMO3 gene can affect the function and quantity of the FMO3 enzyme produced. These genetic changes can range from those that alter single amino acids in the enzyme's structure to those that lead to the production of a truncated, non-functional protein. Such variants can impair the enzyme's ability to process its target compounds effectively.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1118dup | p.Ser374fs | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.1139_1140del | p.Pro380fs | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.1262G>T | p.Gly421Val | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.1498C>T | p.Arg500Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.237del | p.Asn80fs | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.712C>T | p.Arg238Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.713G>A | p.Arg238Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.726_729del | p.Phe242fs | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.778A>G | p.Met260Val | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
c.929C>T | p.Ser310Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Trimethylaminuria |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the FMO3 gene are primarily associated with Trimethylaminuria, also known as fish odour syndrome. This condition is inherited in an autosomal recessive pattern. In individuals with trimethylaminuria, a reduced or absent function of the FMO3 enzyme leads to the accumulation of trimethylamine in the body, which is then released through sweat, urine, and breath, causing a strong fishy odour.
- Trimethylaminuria (fish odour syndrome) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic FMO3 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The FMO3 gene is included in several UK NHS national genomic testing panels. It is listed on the "Likely inborn error of metabolism" panel (R98) and the "Undiagnosed metabolic disorders" panel, both categorised as 'green' indicating strong evidence for its clinical utility within these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the FMO3 gene responsible for?
The FMO3 gene provides instructions for an enzyme that primarily breaks down nitrogen-containing compounds from the diet, such as trimethylamine, in the liver. It also plays a role in metabolising certain medications and chemicals.
What condition is associated with variants in the FMO3 gene?
Variants in the FMO3 gene are associated with Trimethylaminuria, also known as fish odour syndrome. This condition results from the body's inability to properly break down trimethylamine, leading to its accumulation and a characteristic fishy body odour.
How does the FMO3 enzyme process trimethylamine?
The FMO3 enzyme converts trimethylamine, which has a strong fishy smell, into trimethylamine-N-oxide. This converted compound is odourless and is then excreted from the body, typically through urine.
References
- Koukouritaki SB, Poch MT, Henderson MC. Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants. The Journal of pharmacology and experimental therapeutics. 2007. PMID: 17050781
- Zhou J, Shephard EA. Mutation, polymorphism and perspectives for the future of human flavin-containing monooxygenase 3. Mutation research. 2006. PMID: 16481213
- Krueger SK, Vandyke JE, Williams DE. The role of flavin-containing monooxygenase (FMO) in the metabolism of tamoxifen and other tertiary amines. Drug metabolism reviews. 2006. PMID: 16684653
- Bain MA, Fornasini G, Evans AM. Trimethylamine: metabolic, pharmacokinetic and safety aspects. Current drug metabolism. 2005. PMID: 15975041
- Zhang J, Tran Q, Lattard V. Deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene causing trimethylaminuria. Pharmacogenetics. 2003. PMID: 12893987
- Hernandez D, Addou S, Lee D. Trimethylaminuria and a human FMO3 mutation database. Human mutation. 2003. PMID: 12938085
- Zschocke J, Kohlmueller D, Quak E. Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet (London, England). 1999. PMID: 10485731
- Mitchell SC. Trimethylaminuria: susceptibility of heterozygotes. Lancet (London, England). 1999. PMID: 10609842
- Dolphin CT, Janmohamed A, Smith RL. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nature genetics. 1997. PMID: 9398858