Health Safety safety ORIGINAL PAPER IDENTIFICATION OF NEW POSSIBLE GENES INVOLVED IN TRIMETHYLAMINURIA Rosalia D’Angelo1,2, Federica Monastra1, Concetta Scimone1,2, Simona Alibrandi1, Luigi Donato1,2, Antonina Sidoti1,2. 1Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy 2Department of Vanguard Medicine and Therapies, Biomolecular Strategies and Neuroscience, I.E.ME.S.T., Palermo, rity/ sec Italy - and - CORRESPONDANCE: Received: Dec 4th, 2019 safety Rosalia D’Angelo Revised: Dec 9th 2019 - e-mail: [email protected] Accepted: Dec 10th, 2019. Phone number: +390902213372 w.iemest.eu/life Abstract other genes, related to FMO3, possibly involved Trimethylaminuria, also known as “fish odor in the etiopathogenesis of the trimethylaminuria. syndrome” is an inherited disease characterized https://ww by the accumulation, and consequently, by the Key Words: TMAU, bioinformatics, analysis, excretion of trimethylamine which is the causative genes. compound responsible for the unpleasant odor. nline at Due to this malodorous condition, patients are Introduction devastating from a psychosocial perspective Trimethylaminuria is an inherited metabolic being they marginalized in society. The cause of syndrome, characterized by the accumulation the syndrome is rooted in the dysfunctional and the excretion of trimethylamine, a diet o Available metabolism of trimethylamine that can be caused compound which is excreted through urine, by a dysbiosis related to gut microbiota or by a sweat, breath, and other body secretions, causing deficiency in flavin monooxygenase 3 (FMO3), an unpleasant rotten fish odor. This pathological the essential enzyme for the metabolism of condition, as reported in many scientific reviews, trimethylamine. Nowadays there are reliable is uncommon in the society, and due to the fish diagnostic tests based on genetic analysis of odor, affected people are often marginalized. FMO3 gene and on the evaluation of This social impact may represent the first cause trimethylamine concentration measured in the of the psychiatric conditions as depression, urine. Although there is no therapy, many simple anxiety, behavior disorders that affect people treatment options exist that may drastically with trimethylaminuria, as statistical studies have improve the quality of life of these patients. In shown. The patients feel shame and this paper we provide an approach to identify embarrassment, fail to maintain relationships, December 2019 | Volume 7 | ISSUE 2| ©LIFE SAFETY AND SECURITY ISSN: 2283-7604| DOI: 10.12882/2283-7604.2019.7.2 167 avoid contact with people who comment on their 1q24.3 and it counts 10 exons. It encodes for a condition and are obsessive about masking the transmembrane protein localized to the odor with hygiene products and even smoking. endoplasmic reticulum of many tissues, especially Moreover, the malodorous aspect can have in the liver, and it is involved in the metabolism serious and destructive effects also on schooling, of many compounds. In particular, this enzyme personal life, career and relationships, resulting catalyzes the NADPH-dependent oxygenation of in social isolation, low self-esteem and suicide. various nitrogen-, sulfur-, and phosphorous- The first case of trimethylaminuria was published containing xenobiotics such as therapeutic drugs, in 1970 in “The Lancet” by a group of researchers pesticides, and dietary compounds like in Colorado, where they have tested this trimethylamine and tyramine. By the way, the condition in a child who gave off a strong fish FMO3 enzyme catalyzes the N-oxygenation of odor, by finding in his urine a huge level of trimethylamine in trimethylamine-N-oxide, which trimethylamine. In addition, in one of the is inodorous. Trimethylamine is an organic Shakespeare’s plays and in the epic novel compound synthesized by gut microbiota after “Mahabharata”, are described cases of people the ingestion of specific choline-rich food, such as rity/ that smell of rotten fish. The metabolic and red meat, eggs, fishes, legumes. This kind of food sec clinical manifestations of trimethylaminuria are contains compounds like lecithin, choline and L- - and generally regarded as benign, as there is no carnitine that represent the substrates of gut - associated organ dysfunction. Some patients may microbiota to synthesize trimethylamine. Once safety suffer of hypertension. This designation, and the synthesized, trimethylamine is absorbed into the - evidence that the condition is often unrecognized bloodstream [2,3] and then it is converted in by doctors, can have important consequences on trimethylamine-N-oxide by the enzyme FMO3, the delayed or missed diagnosis [1]. localized in the hepatocytes. The gut microbiota There are different types of trimethylaminuria, involved in the production of trimethylamine is but the most common is Type 1 composed by a group of commensal Gram- w.iemest.eu/life trimethylaminuria, caused by a deficit of the positive bacteria that present a large variety of FMO3 enzyme. Consequently, when the enzyme that are able to convert diet precursors pathological condition is suspected or known to in trimethylamine. Mutations in the FMO3 gene occur in a family, the genetic test of theFMO3 cause trimethylaminuria and many mutations https://ww gene, can be helpful in identifying members who were reported as causative of trimethylaminuria have the disorder or any carry causative variant [4,5]. Nonsense and missense mutations cause nline at [1]. In particular, most cases of trimethylaminuria the most severe phenotypes. Although FMO3 appear to be inherited in an autosomal recessive mutations account for most known cases of pattern, which means two copies of the gene in trimethylaminuria, some cases are caused by each cell are altered. The parents of an individual other factors. A fish-like body odor could result o Available with an autosomal recessive disorder are both from an excess of certain proteins in the diet or carriers of one copy of the altered gene. Carriers from increased bacteria in the digestive system. may have mild symptoms of trimethylaminuria or Type 2 TMAU, indeed, is caused by a dysbiosis of experience temporary episodes of fish-like body the gut microbiota. Few cases of the disorder odor. In addition, measurement of urine for the have been identified in adults with liver damage ratio of trimethylamine is the standard screening caused by hepatitis. This condition is known as test. The FMO3 enzyme, also known as Flavin- acquired trimethylaminuria urinary tract containing monooxygenase 3, is encoded by the infection, bacterial vaginosis, cervical cancer, FMO3 gene. The gene FMO3 belongs to the advanced kidney disease can be external factors family of FMO genes, made up by five genes and that can distort TMAU diagnosis [6]. multiple pseudogenes, differentially expressed in A specific form of the disease was diagnosed in tissues. FMO3 is located on the chromosome children and it is known as “Childhood December 2019 | Volume 7 | ISSUE 2| ©LIFE SAFETY AND SECURITY ISSN: 2283-7604| DOI: 10.12882/2283-7604.2019.7.2 168 trimethylaminuria”. It is caused by a transitory Methods reduction of the FMO3 expression in children. We have used a bioinformatic approach to Usually, in children is expressed the fetal isoform identify new genes probably involved in the of FMO, that is FMO1 rather than FMO3. etiopathogenesis of trimethylaminuria. In In addition, other factors can worsen the particular, we used the Cytoscape platform in pathological condition. In particular, female sex order to obtain and characterize molecular hormones as progesterone and estrogen could network of the FMO3 gene. Cytoscape is an open influence negatively and positively the FMO3 source software platform for visualize molecular expression, respectively. According to several interaction networks and biological pathways and reports, the condition worsens around puberty. allows to integrate these networks with In women, symptoms may worsen just before annotations, gene expression profiles and other and during menstrual periods, after taking oral state data. Cytoscape core distribution provides a contraceptives, and during menopause [7]. basic set of features for data integration, analysis, So, in conclusion, the odor depends on various and visualization. Additional features are factors, such as diet, hormonal changes, stress available as Apps (formerly called Plugins). Apps rity/ level, amount of sweat. There is no known are available for network and molecular profiling sec therapy or treatment for the disorder and the analyses, new layouts, additional file format - and ways to reduce the fishy odor may include support, scripting, and connection with - avoiding foods such as egg yolks, legumes, red databases. Among the apps, we used GeneMania. safety meats, fish, beans and other foods that contain The GeneMania Cytoscape plugin brings fast gene - choline, carnitine, nitrogen, sulfur and lecithin function prediction capabilities to the desktop taking low doses of antibiotics such as neomycin and it identifies the most related genes to a and metronidazole [8] in order to reduce the query gene set using a guilt-by-association amount of bacteria in the gut; approach. The plugin uses a large database of using slightly acidic detergent with a pH between functional interaction networks from multiple w.iemest.eu/life 5.5 and 6.5. organisms and each related gene is traceable to Additionally,