Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FMO3) gene in patients with fish-odour syndrome

Fish-odour syndrome is a highly unpleasant disorder of hepatic trimethylami ne (TMA) metabolism characterized by a body odour reminiscent of rotting fi sh, due to excessive excretion of the malodorous free amine, Although fish- odour syndrome may exhibit as sequelae. With other conditions (e.g. liver d ysfunction), many patients exhibit an inherited, more persistent form of th e disease, Ordinarily, dietary-derived TMA is oxidized to the non-odorous N -oxide by hepatic flavin-containing monooxygenase 3 (FMO3), Our previous de monstration that a mutation, P153L (C to T), in the FMO3 gene segregated wi th the disorder and inactivated the enzyme confirmed that defects in FMO3 u nderlie the inherited form of fish-odour syndrome, We have investigated the genetic basis of the disorder in two further affected pedigrees and report that the three propositi are all compound heterozygotes for causative muta tions of FMO3. Two of these individuals possess the P153L (C to T) mutation and a novel mutation, N61S (A to G), The third is heterozygous for novel, M434I (G to A), and previously reported, R492W (C to T), mutations. Functio nal characterization of the S61, I434 and W492 variants, via baculovirus-me diated expression in insect cells, confirmed that all three mutations eithe r abolished, or severely attenuated, the capacity of the enzyme to catalyse TMA N-oxidation. Although I434 and W492 were also incapable of catalysing the S-oxidation of methimazole, S61 was fully active with this sulphur-cont aining substrate. Since an asparagine is conserved at the equivalent positi on to N61 of FMO3 in mammalian, yeast and Caenorhabditis elegans FMOs, the characterization of the naturally occurring N61S (A to G) mutation may have identified this asparagine as playing a critical role specifically in FMO- catalysed N-oxidation. Pharmacogenetics 10:799-807 (C) 2000 Lippincott Will iams & Wilkins.