Alternative titles; symbols
HGNC Approved Gene Symbol: FMO3
SNOMEDCT: 237959005; ICD10CM: E72.52;
Cytogenetic location: 1q24.3 Genomic coordinates (GRCh38) : 1:171,090,905-171,117,819 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.3 | Trimethylaminuria | 602079 | Autosomal recessive | 3 |
The mammalian flavin-containing monooxygenases (FMO; EC 1.14.13.8) represent a multigene family whose gene products are localized in the endoplasmic reticulum of many tissues. These enzymes catalyze the NADPH-dependent oxidative metabolism of many drugs, pesticides, and other foreign compounds. Their substrates are soft nucleophiles with an electron-rich center, typically a nitrogen, sulfur or phosphorus-containing functional group, as the site for oxidative attack by the enzyme (Ziegler, 1990; Hines et al., 1994).
Lomri et al. (1992) isolated a full-length cDNA sequence for FMO3, which they designated FMO II, from an adult human liver cDNA library. This cDNA encoded a deduced 533-amino acid protein.
Dolphin et al. (1996) also isolated an FMO3 cDNA from a human liver library. This cDNA encoded a deduced 532-amino acid protein that shared 84% sequence identity with the rabbit FMO3 protein.
Dolphin et al. (1997) determined that the FMO3 gene contains 1 noncoding and 8 coding exons.
By use of PCR with DNAs from somatic cell hybrids, Shephard et al. (1993) mapped the FMO3 gene to chromosome 1. FMO3 is probably located in a cluster with FMO1 (136130) and FMO4 (136131) at 1q23-q25.
Using quantitative RNase protection assays, Phillips et al. (1995) and Dolphin et al. (1996) determined that FMO3 is present in low abundance in fetal liver and lung and in adult kidney and lung, and in much greater abundance in adult liver. They determined that FMO3 and FMO1 (136130) are subject to developmental and tissue-specific regulation and, in the liver, there is a developmental switch in the expression of these genes.
By Western blot analysis of human liver microsomal samples ranging from 8 weeks gestation to 18 years of age, Koukouritaki et al. (2002) confirmed that FMO1 is the major fetal isoform and FMO3 is the major adult isoform. The highest level of FMO1 expression was observed in embryonic samples at 8 to 15 weeks of gestation; its expression was low, but detectable in most samples within the first 3 days of life, but then was extinguished in all but a few samples. In contrast, the onset of FMO3 expression was highly variable, with most individuals failing to express this isoform during the neonatal period. FMO3 was expressed at intermediate levels until 11 years of age when a gender-independent increase in FMO3 expression was observed during puberty. Koukouritaki et al. (2002) observed pronounced interindividual variation of FMO3 protein levels from 2- to 20-fold.
Phillips and Shephard (2008) noted that the delay between silencing of the FMO1 gene and the full activation of FMO3 means that during the first year of life many children have no, or very little, drug-metabolizing FMOs in their liver.
Hernandez et al. (2003) pointed out that compromised activity of FMO3 is expected to have implications for the efficacy of drug treatment and the possibility of adverse drug reactions in patients with trimethylaminuria (TMAU; 602079) and in the general population. In addition to metabolizing the dietary-derived amine TMA, FMO3 catalyzes the NADPH-dependent oxidation of numerous foreign compounds, including therapeutic drugs such as the antiestrogen tamoxifen, the antifungal ketoconazole, and the nonsteroidal antiinflammatory drugs sulindac sulfide and benzydamine, as reviewed by Cashman and Zhang (2002). Sufferers of trimethylaminuria may display a reduced ability to metabolize substrates for FMO3 such as nicotine (Ayesh et al., 1988).
FMO3 metabolizes a number of drugs, including amphetamine, clozapine, deprenyl, metamphetamine, tamoxifen, ethionamide, thiacetazone, and sulindac sulfide (see reviews by Krueger and Williams (2005) and Phillips and Shephard (2008)).
Akerman et al. (1997) and Treacy et al. (1998) reported 3 different mutations in the FMO3 gene in Australian probands with trimethylaminuria (602079), or fish-odor syndrome, who shared a particular polymorphic haplotype. Treacy et al. (1998) showed that these mutations impair N-oxygenation of xenobiotics and are responsible for the trimethylaminuria phenotype. A nonsense mutation, glu305 to ter (E305X; 136132.0001), was found on 6 mutant chromosomes of British origin, homozygous in 1 and heterozygous in 4 individuals. Homozygosity for a missense mutation, val257 to met (V257M; 136132.0002), was found in 1 individual of Greek origin. Heterozygosity for a met66-to-ile (M66I; 136132.0003) mutation was found in 1 individual of Irish extraction.
In a patient with trimethylaminuria, Dolphin et al. (1997) found a pro153-to-leu mutation in the FMO3 gene (P153L; 136132.0004) that abolished FMO3 catalytic activity. They demonstrated that FMO3 with the 551C-T mutation could not support the metabolism of dietary-derived trimethylamine (TMA). In addition to TMA, FMOs catalyze the oxidation of a range of structurally diverse compounds, including drugs, pesticides, and other xenobiotics. The authors commented that although patients with trimethylaminuria are apparently deficient in nicotine N-oxidation, a reaction catalyzed predominantly by FMO3, the pharmacologic and toxicologic significance of an inherited block in FMO3-mediated oxidative metabolism is unclear.
Treacy et al. (1998) found that nonsense and missense mutations in the FMO3 gene were associated with a severe trimethylaminuria phenotype and were also implicated in impaired metabolism of other nitrogen- and sulfur-containing substances, including biogenic amines, both clinically and when mutated proteins expressed from cDNA were studied in vitro. The findings illustrated the clinical role played by human FMO3 in the metabolism of xenobiotic substrates and endogenous amines. One patient of English-Irish extraction with severe hypertension was observed with blood pressure of 200/110 following the use of nasal epinephrine. Adverse tyramine reactions were observed in at least 3 patients. Urticaria and intolerance of sulfur-containing medication was observed in a patient homozygous for the P153L mutation.
Chung and Cha (1997) showed that production of theobromine from caffeine is catalyzed primarily by the FMO present in adult human liver microsomes. They determined FMO activity in vivo noninvasively by taking the urinary molar concentration ratio of theobromine/caffeine in a Korean population. In 82 Korean volunteers, Park et al. (1999) determined FMO activity by taking the molar concentration ratio of theobromine and caffeine present in the 1-hour urine (between 4 and 5 hours) samples collected after administration of a cup of coffee containing 110 mg of caffeine. Among 82 volunteers, there were 19 women and 63 men (30 smokers and 52 nonsmokers). Volunteers were divided into 2 groups comprising low (0.53-2.99) and high (3.18-11.95) FMO activities separated by an antimode of 3.18. Genomic DNAs from peripheral blood were amplified by PCR with oligonucleotides designed from intronic sequences of the human FMO3 gene. Comparing nucleotide sequences of the amplified FMO3 gene originating from randomly selected individuals with low and high FMO activities, 9 point mutations were identified in the open reading frame sequences.
Akerman et al. (1999) studied a cohort of North American individuals with severe trimethylaminuria, defined by a reduction of TMA oxidation below 50% of normal. They detected 4 novel FOM3 mutations, including 2 missense mutations, ala52 to thr (A52T; 136132.0008) and arg387 to leu (R387L; 136132.0007), and 1 nonsense mutation, glu314 to ter (E314X; 136132.0009). The fourth allele was apparently composed of 2 relatively common polymorphisms (lys158-gly308) found in the general population. For the E314X mutation, loss of activity was strongly predicted due to truncation of the FMO3 protein at codon 314, since deletion of even the final 30 amino acids of this 532-residue protein will ablate function in vitro. While the A52T and R387L mutations had not been expressed, they satisfied several conditions for designation as disease-causing: the changes were not observed in controls, they were nonconservative substitutions, and no other changes were identified in the probands when sequencing all expressed FMO3 exons. Furthermore, the A52T and R387L residues appear to be highly conserved within the FMO gene family. The authors suggested that the 2 common changes (lys158-gly308) in cis diminished the activity of the enzyme and rendered it incapable of compensating for the A52T mutation carried by the other allele.
Hernandez et al. (2003) described a human FMO3 mutation database. They indicated that 16 mutations (12 missense, 3 nonsense, and 1 gross deletion) were known to cause trimethylaminuria.
Akerman et al. (1997) identified a glu305-to-ter (E305X) mutation in the FMO3 gene in 6 mutant chromosomes from Australian probands of British origin with trimethylaminuria (TMAU; 602079). The mutation was homozygous in 1 and heterozygous in 4 individuals. The E305X homozygote had, in addition to trimethylaminuria, tachycardia and severe hypertension after eating cheese (which contains tyramine) and after using nasal epinephrine in the treatment of an epistaxis (Danks et al., 1976). The FMO3 enzyme metabolizes tyramine. Mutant FMO3 cDNA for this mutation demonstrated loss of substrate activity for TMA and tyramine when expressed in E. coli.
In an Australian individual of Greek origin with trimethylaminuria (TMAU; 602079), Akerman et al. (1997) found homozygosity for a val257-to-met (V257M) missense mutation in the FMO3 gene.
In an Australian individual of Irish origin with trimethylaminuria (TMAU; 602079), Akerman et al. (1997) found a met66-to-ile (M66I) mutation in the FMO3 gene in heterozygous state. Mutant FMO3 cDNA containing the M66I substitution demonstrated loss of substrate activity for TMA and tyramine when expressed in E. coli.
In an Australian patient with trimethylaminuria, Akerman et al. (1999) found compound heterozygosity for 2 missense mutations in the FMO3 gene: M66I and arg492 to trp (R492W; 136132.0005). The second of these mutations involved a hypermutable CpG site and was a nonconservative change in a highly conserved region of the FMO3 gene. Arg492 was conserved in all FMO isoforms.
In a brother and sister with trimethylaminuria (TMAU; 602079), Dolphin et al. (1997) identified a homozygous 551C-T transition in the FMO3 gene, changing a CCC proline triplet at codon 153 to a CTC leucine triplet (P153L). Their unaffected parents and a third sib were heterozygous for the mutation. The authors found the same mutation in 2 other trimethylaminuria kindreds, in which it also cosegregated with the disorder. In the first kindred studied, the leu153 allele was found to carry a polymorphism at codon 158, namely glu158. Among 30 unrelated, non-trimethylaminuric individuals, pro153 was found in all, whereas glu158 and lys158 occurred in frequencies of approximately 50% each.
For discussion of the arg492-to-trp (R492W) mutation in the FMO3 gene that was found in compound heterozygous state in a patient with trimethylaminuria (TMAU; 602079) by Akerman et al. (1999), see 136132.0003.
Park et al. (1999) determined FMO activity by taking the molar concentration ratio of theobromine and caffeine present in the 1-hour urine (between 4 and 5 hours) samples collected after administration of a cup of coffee containing 110 mg of caffeine. In an individual who had the second lowest FMO activity, they detected a missense mutation, 442G-T in exon 4, that yielded a premature TGA stop codon replacing glycine-148 (G148X). He had the mutation in heterozygous state. His mother also had the heterozygous stop codon and equally low FMO activity.
In a Metis patient from Canada with trimethylaminuria (TMAU; 602079), Akerman et al. (1999) found homozygosity for a G-to-T transversion at nucleotide 1160 of the FMO3 gene, resulting in an arg387-to-leu (R387L) mutation.
In a North American patient with trimethylaminuria (TMAU; 602079), Akerman et al. (1999) identified a G-to-A transition at nucleotide 154 of the FMO3 gene, resulting in an ala52-to-thr (A52T) mutation.
In a North American patient with trimethylaminuria (TMAU; 602079), Akerman et al. (1999) identified a G-to-T transversion at nucleotide 940 of the FMO3 gene, resulting in a glu314-to-ter (E314X) substitution.
Dolphin et al. (2000) found 2 individuals with trimethylaminuria (TMAU; 602079) who were compound heterozygous for the P153L missense mutation (136132.0004) and a novel asn61-to-ser (N61S) mutation in the FMO3 gene.
Dolphin et al. (2000) found that a patient with trimethylaminuria (602079) was compound heterozygous for the R492W mutation (136132.0005) and a novel met434-to-ile (M434I) mutation in the FMO3 gene.
Forrest et al. (2001) described trimethylaminuria (TMAU; 602079) caused by a deletion of more than 12 kb in the FMO3 gene in a 15-year-old Australian male of Greek parents. The deletion began 328 bp upstream from exon 1; the 3-prime end of the deletion occurred in intron 2. The deletion was 12,226 bp long. Because of homozygosity for the FMO3 gene deletion, it was predicted that in addition to loss of monooxygenase function for human FMO3 substrates, such as trimethylamine and other amines, the proband would exhibit decreased tolerance of biogenic amines, both medicinal and dietary.
In a patient with trimethylaminuria (TMAU; 602079), Zhang et al. (2003) identified a glu32-to-lys (E32K) mutation in the FMO3 gene. Expression studies showed that the E32K mutation abrogated the catalytic activity of the enzyme.
In an individual with trimethylaminuria (TMAU; 602079), Zhang et al. (2003) identified compound heterozygosity for 2 mutations in the FMO3 gene: a P153L change (136132.0004) and a 1-bp deletion (191delA) in exon 3 at codon 64. The deletion resulted in a frameshift and premature termination of the gene immediately after codon 65. Family pedigree analysis revealed that the 2 mutations were carried on different alleles in this individual. Both mutations abolished the catalytic activity of the enzyme, explaining the severe clinical expression of trimethylaminuria. The patient was examined at the age of 3 years, at which time he was found to have 61% unmetabolized trimethylamine in urine, compatible with severe trimethylaminuria.
In patients with mild trimethylaminuria (TMAU; 602079), Zschocke et al. (1999) identified compound heterozygosity for mutations in the FMO3 gene: a P151L substitution (136132.0004) on one allele, and 2 common polymorphisms, glu308 to gly (E308G) and glu 158 to lys (E158K), on the other. Zschocke et al. (1999) noted that homozygosity for the P151L mutation had been found to cause severe trimethylaminuria. They found that individuals homozygous for the variant allele with the 2 common polymorphisms had decreased TMA oxidation capacity (less than 50%) indicative of mild trimethylaminuria.
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