Objectives: Trimethylaminuria (TMAuria; MIM 602079) is an autosomal recessive condition caused by a partial or total incapacity to catalyze the N-oxygenation of the odorous compound trimethylamine (TMA) by FMO3.The result is a severe body odor and associated psychosocial conditions. Several polymorphic variants of FMO3 have been identified (1-2). Individually, these have little or no effect on enzyme activity. However, the haplotype with two polymorphisms in cis seems to cause a reduction of enzyme activity (3-4). A 5-year- old Italian girl with diagnosis of suspected trimethylaminuria has come to our attention.To detect variants causative for TMAuria, we perform a genetic analysis in the patient and family’s members, all not complaining for a body odor. Methods: Upstream sequence of the FMO3 gene, the non-coding exon 1 and each of the coding exons were amplified by PCR using the specific primer pairs. Amplified products were sequenced on the 377 ABI PRISM Sequencer Analyzer. Results: The child and her parents were found to be heterozygous for three polymorphic variants, already reported in literature as causing a sensible reduction of enzyme activity.The child’s brother lacked these variants. Conclusion: Like the parents, the child is thus a carrier of the disorder. However, in contrast to her parents, she displays symptoms of TMAuria. It is likely that the child suffers from transient childhood TMAuria. Expression of the FMO3 gene is switched on within two years after birth and continues to increase throughout childhood (5). Thus, a combination of one non-functional FMO3 allele and immature expression of the other, functional, FMO3 allele, is often sufficient to cause symptoms of the disorder.Furthermore it is possible that dietary variations contribute to differences in symptoms between child and her and parents. References: 1. I.R. Phillips, A.A. Francois, et al. Pharmacogenomics 5 (2007),292–313 2.S.B. Koukouritaki, R.N. Hines, et al. Pharmacogenomics 6 (2005),807–22 3. V. Lattard, J. Zhang, et al. Drug Metab Dispos 31(2003),854–60 4. M. Shimizu, H. Yano, et al. Drug Metab. Dispos 35 (2007),328–30 5. S.B. Koukouritaki, P. Simpson, et al. Pediatr Res 51 (2002), 236–43

A MOLECULAR- GENETIC ANALYSIS OF FLAVIN-CONTAINING MONOOXYGENASE3 GENE (FMO3) IN AN ITALIAN CHILD WITH A TMAURIA LIKE-PHENOTYPE

C. Scimone;RUGGERI, ALESSIA;BRUSCHETTA, Daniele;RINALDI, Carmela;D'ANGELO, Rosalia;SIDOTI, Antonina
2014

Abstract

Objectives: Trimethylaminuria (TMAuria; MIM 602079) is an autosomal recessive condition caused by a partial or total incapacity to catalyze the N-oxygenation of the odorous compound trimethylamine (TMA) by FMO3.The result is a severe body odor and associated psychosocial conditions. Several polymorphic variants of FMO3 have been identified (1-2). Individually, these have little or no effect on enzyme activity. However, the haplotype with two polymorphisms in cis seems to cause a reduction of enzyme activity (3-4). A 5-year- old Italian girl with diagnosis of suspected trimethylaminuria has come to our attention.To detect variants causative for TMAuria, we perform a genetic analysis in the patient and family’s members, all not complaining for a body odor. Methods: Upstream sequence of the FMO3 gene, the non-coding exon 1 and each of the coding exons were amplified by PCR using the specific primer pairs. Amplified products were sequenced on the 377 ABI PRISM Sequencer Analyzer. Results: The child and her parents were found to be heterozygous for three polymorphic variants, already reported in literature as causing a sensible reduction of enzyme activity.The child’s brother lacked these variants. Conclusion: Like the parents, the child is thus a carrier of the disorder. However, in contrast to her parents, she displays symptoms of TMAuria. It is likely that the child suffers from transient childhood TMAuria. Expression of the FMO3 gene is switched on within two years after birth and continues to increase throughout childhood (5). Thus, a combination of one non-functional FMO3 allele and immature expression of the other, functional, FMO3 allele, is often sufficient to cause symptoms of the disorder.Furthermore it is possible that dietary variations contribute to differences in symptoms between child and her and parents. References: 1. I.R. Phillips, A.A. Francois, et al. Pharmacogenomics 5 (2007),292–313 2.S.B. Koukouritaki, R.N. Hines, et al. Pharmacogenomics 6 (2005),807–22 3. V. Lattard, J. Zhang, et al. Drug Metab Dispos 31(2003),854–60 4. M. Shimizu, H. Yano, et al. Drug Metab. Dispos 35 (2007),328–30 5. S.B. Koukouritaki, P. Simpson, et al. Pediatr Res 51 (2002), 236–43
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11570/2984768
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