A spectrum of molecular variation in a cohort of Italian families with trimethylaminuria: identification of three novel mutations of the FM03 gene.

Fish-odor syndrome or trimethylaminuria, is a rare inborn error of metabolism inherited in an autosomal recessive fashion, involving the dysfunction of hepatic enzyme flavin-containing monooxygenase 3 (FMO3) that converts fishy-smelling trimethylamine (TMA) into odorless trimethylamine-N-oxide (TMAO). This confers, to the affected individual a very unpleasant body odor resembling that of rotting fish. This disorder has been relatively well-documented in British, Australian, and American populations and reports have appeared regarding patients in Thailand and Hong Kong, but no Italian families affected by trimethylaminuria have been reported in the literature. We have collected a cohort of Italian families and investigated the genetic basis of the disorder in these Italian pedigrees disclosing a spectrum of molecular variation in the FM03 gene comprising three novel deleterious mutations: the first documented de novo missense mutation causative of trimethylaminuria; a guanidine nucleotide deletion (G1182del) at codon 394 and a novel missense mutation (R238P) that altered highly conserved amino acid in the exon 6. Moreover, we investigated by aplotype analysis a family with mild TMAuria identifying a putative causative aplotype. Finally, we failed to detect any variation in other Italian families suggesting that this gene is not associated with all clinical form of trimethylaminuria or that polymorphisms in this gene could be susceptibility factors for developing the disease. Our findings support the hypothesis that TMAuria is not a rare recessive disorder but rather a spectrum of malodour phenotypes in which diet and environmental exposures can play a role in triggering symptoms.