A novel mutation in the flavin-containing monooxygenase 3 gene (FMO3) of a Norwegian family causes trimethylaminuria

Molecular Genetics and Metabolism

Volumn 98, Issue 1-2, 2009, Pages 198-202

  Allerston, C K ^a   Vetti, H H ^b   Houge, G ^b   Phillips, I R ^c   Shephard, E A ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b HAUKELAND UNIVERSITY HOSPITAL   (Norway)

^c QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

Fish odour syndrome; Flavin containing monooxygenase; FMO3; Mutation; Norway; Trimethylaminuria

Indexed keywords

DIMETHYLANILINE MONOOXYGENASE; FLAVIN CONTAINING MONOOXYGENASE 3; MUTANT PROTEIN; UNCLASSIFIED DRUG;

ARTICLE; BACTERIUM; DNA DETERMINATION; ENZYME MECHANISM; EXON; FAMILIAL DISEASE; FEMALE; FMO3 GENE; GENE; GENE MUTATION; GENETIC COUNSELING; GENETIC VARIABILITY; HETEROZYGOSITY; HOMOZYGOSITY; HUMAN; MALE; NORWAY; NUCLEOTIDE SEQUENCE; ODOR; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; TRIMETHYLAMINURIA;

ALLELES; AMINO ACID SEQUENCE; BASE SEQUENCE; BIOCATALYSIS; DNA MUTATIONAL ANALYSIS; EUROPEAN CONTINENTAL ANCESTRY GROUP; EXONS; FAMILY; FEMALE; HUMANS; KINETICS; MALE; METABOLISM, INBORN ERRORS; MOLECULAR SEQUENCE DATA; MUTANT PROTEINS; MUTATION; NORWAY; OXYGENASES; PEDIGREE; PROTEIN STRUCTURE, SECONDARY;

EID: 67651218957     PISSN: 10967192     EISSN: 10967206     Source Type: Journal    
DOI: 10.1016/j.ymgme.2009.06.002     Document Type: Article

References (45)

1. Krueger S.K., and Williams D.E. Mammalian flavin-containing monooxygenases: Structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol. Ther. 106 (2005) 357-387
2. Cashman J.R., and Zhang J. Human flavin-containing monooxygenases. Annu. Rev. Pharmacol. Toxicol. 46 (2006) 65-100
3. Phillips I.R., Francois A.A., and Shephard E.A. The flavin-containing monooxygenases (FMOs): genetic variation and its consequences for the metabolism of therapeutic drugs. Curr. Pharmacogenomics 5 (2007) 292-313
4. Phillips I.R., Dolphin C.T., Clair P., Hadley M.R., Hutt A.J., McCombie R.R., Smith R.L., and Shephard E.A. The molecular biology of the flavin-containing monooxygenases of man. Chem. Biol. Interact. 96 (1995) 17-32
5. Shephard E.A., Dolphin C.T., Fox M.F., Povey S., Smith R., and Phillips I.R. Localization of genes encoding three distinct flavin-containing monooxygenases to human chromosome 1q. Genomics 16 (1993) 85-89
6. McCombie R.R., Dolphin C.T., Povey S., Phillips I.R., and Shephard E.A. Localization of human flavin-containing monooxygenase genes FMO2 and FMO5 to chromosome 1q. Genomics 34 (1996) 426-429
7. Hernandez D., Janmohamed A., Chandan P., Phillips I.R., and Shephard E.A. Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters. Pharmacogenetics 14 (2004) 117-130
8. Haining R.L., Hunter A.P., Sadeque A.J., Philpot R.M., and Rettie A.E. Baculovirus-mediated expression and purification of human FMO3: catalytic, immunochemical, and structural characterization. Drug Metab. Disp. 25 (1997) 790-797
9. Dolphin C.T., Janmohamed A., Smith R.L., Shephard E.A., and Phillips I.R. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat. Genet. 17 (1997) 491-494
10. Treacy E.P., Akerman B.R., Chow L.M.L., Youil R., Bibeau C., Lin J., Bruce A.G., Knight M., Danks D.M., Cashman J.R., and Forrest S.M. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum. Mol. Genet. 7 (1998) 839-845
11. I.R. Phillips, E.A. Shephard, Trimethylaminuria, in: GeneReviews at GeneTests: Medical Genetics Information Resource (database online) Copyright, University of Washington, Seattle 1997-2007. Available from: .
12. Phillips I.R., and Shephard E.A. Flavin-containing monooxygenases: mutations, Disease and drug response. Trends Pharmacol. Sci. 29 (2008) 294-301
13. Al-Waiz M., Ayesh R., Mitchell S.C., Idle J.R., and Smith R.L. Trimethylaminuria ('fish-odour syndrome'): a study of an affected family. Clin. Sci. 74 (1988) 231-236
14. Cashman J.R., Camp K., Fakharzadeh S.S., Fennessey P.V., Hines R.N., Mamer O.A., Mitchell S.C., Nguyen G.P., Schlenk D., Smith R.L., Tjoa S.S., Williams D.E., and Yanicelli S. Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Curr. Drug Metab. 4 (2003) 151-170
15. Hernandez D., Addou S., Lee D., Orengo C., Shephard E.A., and Phillips I.R. Trimethylaminuria and a human FMO3 mutation database. Hum. Mut. 22 (2003) 201-213
16. Koukouritaki S.B., and Hines R.N. Flavin-containing monooxygenase genetic polymorphism: impact on chemical metabolism and drug development. Pharmacogenomics 6 (2005) 807-822
17. Lattard V., Zhang J., Tran Q., Furnes B., Schlenk D., and Cashman J.R. Two new polymorphisms of the FMO3 gene in Caucasian and African-American populations: Comparative genetic and functional studies. Drug Metab. Dispos. 31 (2003) 854-860
18. Cashman J.R. The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development. Drug Discov. Today 9 (2004) 574-581
19. Shimizu M., Yano H., Nagashima S., Murayama N., Zhang J., Cashman J.R., and Yamazaki H. Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activities. Drug Metab. Dispos. 35 (2007) 328-330
20. Mayatepek E., and Kohlmüller D. Transient trimethylaminuria in childhood. Acta Paediatrica 87 (1998) 1205-1207
21. Koukouritaki S.B., Simpson P., Yeung C.K., Rettie A.E., and Hines R.N. Human hepatic flavin-containing monooxygenases 1 (FMO1) and 3 (FMO3) developmental expression. Pediatr. Res. 51 (2002) 236-243
22. Zhang A.Q., Mitchell S.C., and Smith R.L. Exacerbation of symptoms of fish-odour syndrome during menstruation. Lancet 348 (1996) 1740-1741
23. Shimizu M., Cashman J.R., and Yamazaki H. Transient trimethylaminuria related to menstruation. BMC Med. Genet. 8 (2007) 2
24. Coecke S., Debast G., Phillips I.R., Vercruysse A., Shephard E.A., and Rogiers V. Hormonal regulation of microsomal flavin-containing monooxygenase activity by sex steroids and growth hormone in co-cultured adult male rat hepatocytes. Biochem. Pharmacol. 56 (1998) 1047-1051
25. Mitchell S.C., and Smith R.L. Trimethylaminuria: the fish malodor syndrome. Drug Metab. Dispos. 29 (2001) 517-521
26. Dolphin C.T., Cullingford T.E., Shephard E.A., Smith R.L., and Phillips I.R. Differential developmental and tissue-specific regulation of expression of the genes encoding three members of the flavin-containing monooxygenase family of man, FMO1, FMO3 and FMO4. Eur. J. Biochem. 235 (1996) 683-689
27. Dixit A., and Roche T.E. Spectrophotometric assay of the flavin-containing monooxygenase and changes in its activity in female mouse liver with nutritional and diurnal conditions. Arch. Biochem. Biophys. 233 (1984) 50-63
28. Dolphin C.T., Beckett D.J., Janmohamed A., Cullingford T.E., Smith R.L., Shephard E.A., and Phillips I.R. The flavin-containing monooxygenase 2 gene (FMO2) of humans, but not of other primates, encodes a truncated, nonfunctional protein. J. Biol. Chem. 273 (1998) 30599-30607
29. Dolphin C.T., Riley J.H., Smith R.L., Shephard E.A., and Phillips I.R. Structural organization of the human flavin-containing monooxygenase 3 gene (FMO3), the favored candidate for fish-odor syndrome, determined directly from genomic DNA. Genomics 46 (1997) 260-267
30. Koukouritaki S.B., Poch M.T., Cabacungan E.T., McCarver D.G., and Hines R.N. Discovery of novel flavin-containing monooxygenase 3 (FMO3) single nucleotide polymorphisms and functional analysis of upstream haplotype variants. Mol. Pharmacol. 68 (2005) 383-392
31. Sachse C., Ruschen S., Dettling M., Schley J., Bauer S., Muller-Oerlinghausen B., Roots I., and Brockmoller J. Flavin monooxygenase 3 (FMO3) polymorphism in a white population: allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism. Clin. Pharmacol. Ther. 66 (1999) 431-438
32. Kang J.H., Chung W.G., Lee K.H., Park C.S., Kang J.S., Shin I.C., Roh H.K., Dong M.S., Beak H.M., and Cha Y.N. Phenotypes of flavin-containing monooxygenase activity determined by ranitidine N-oxidation are positively correlated with genotypes of linked FMO3 gene mutations in a Korean population. Pharmacogenetics 10 (2000) 67-78
33. Cashman J.R., Zhang J., Leushner J., and Braun A. Population distribution of human flavin-containing monooxygenase form 3: gene polymorphisms. Drug Metab. Dispos. 29 (2001) 1629-1637
34. Park C.S., Kang J.H., Chung W.G., Yi H.G., Pie J.E., Park D.K., Hines R.N., McCarver D.G., and Chan Y.N. Ethnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: Linkage and effects on in vivo and in vitro FMO activities. Pharmacogenetics 12 (2002) 77-80
35. Allerston C.K., Shimizu M., Fujieda M., Shephard E.A., Yamazaki H., and Phillips I.R. Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3). Pharmacogenet. Genomics 17 (2007) 827-839
36. Zschocke J., Kohlmueller D., Quak E., Meissner T., Hoffmann G.F., and Mayatepek E. Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet 354 (1999) 834-835
37. Francois A.A., Nishida C.R., de Montellano P.R., Phillips I.R., and Shephard E.A. Human flavin-containing monooxygenase 2.1 catalyzes oxygenation of the antitubercular drugs thiacetazone and ethionamide. Drug Metab. Dispos. 37 (2009) 178-186
38. Falls J.G., Cherrington N.J., Clements K.M., Philpot R.M., Levi P.E., Rose R.L., and Hodgson E. Molecular cloning, sequencing, and expression in Escherichia coli of mouse flavin-containing monooxygenase 3 (FMO3): comparison with the human isoform. Arch Biochem. Biophys. 347 (1997) 9-18
39. Teresa E., Lonardo F., Fiumara A., Lombardi C., Russo P., Zuppi C., Scarano G., Musumeci S., and Gianfrancesco F. A spectrum of molecular variation in a cohort of Italian families with trimethylaminuria: Identification of three novel mutations of the FMO3 gene. Mol. Genet. Metab. 88 (2006) 192-195
40. Dolphin C.T., Janmohamed A., Smith R.L., Shephard E.A., and Phillips I.R. Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FMO3) gene in patients with fish-odour syndrome. Pharmacogenetics 10 (2000) 799-807
41. Koukouritaki S.B., Poch M.T., Henderson M.C., Siddens L.K., Krueger S.K., VanDyke J.E., Williams D.E., Pajewski N.M., Wang T., and Hines R.N. Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants. J. Pharmacol. Exp. Ther. 320 (2007) 266-273
42. Alfieri A., Malito E., Orru R., Fraaije M.W., and Mattevi A. Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase. Proc. Natl. Acad. Sci. USA 105 (2008) 6572-6577
43. Furnes B., Feng J., Sommer S.S., and Schlenk D. Identification of novel variants of the flavin-containing monooxygenase gene family in African Americans. Drug Metab. Dispos. 31 (2003) 187-193
44. Veeramah K., Thomas M.G., Weale M.E., Zeitlyn D., Tarekegn A., Bekele E., Mendel N.R., Shephard E.A., Bradman N., and Phillips I.R. The potentially deleterious functional variant flavin-containing monooxygenase 2*1 is at high frequency throughout sub-Saharan Africa. Pharmacogenet. Genomics 18 (2008) 877-886
45. Vockley J., Rinaldo P., Bennett M.J., Matern D., and Vladutiu G.D. Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways. Mol. Genet. Metab. 71 (2000) 10-18