Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes

Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of...

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Autores principales:	Simona Alibrandi, Fabiana Nicita, Luigi Donato, Concetta Scimone, Carmela Rinaldi, Rosalia D’Angelo, Antonina Sidoti
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>FMO3</i> TMAU in silico proteomics genetic variants Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/b47719394e884891aed29167725e8868
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spelling	oai:doaj.org-article:b47719394e884891aed29167725e88682021-11-25T18:29:24ZAdaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes10.3390/molecules262270451420-3049https://doaj.org/article/b47719394e884891aed29167725e88682021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/7045https://doaj.org/toc/1420-3049Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene <i>FMO3</i>, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The <i>FMO3</i> screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of <i>FMO3</i>, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of <i>FMO3</i> variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis.Simona AlibrandiFabiana NicitaLuigi DonatoConcetta ScimoneCarmela RinaldiRosalia D’AngeloAntonina SidotiMDPI AGarticle<i>FMO3</i>TMAUin silicoproteomicsgenetic variantsOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 7045, p 7045 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>FMO3</i> TMAU in silico proteomics genetic variants Organic chemistry QD241-441
spellingShingle	<i>FMO3</i> TMAU in silico proteomics genetic variants Organic chemistry QD241-441 Simona Alibrandi Fabiana Nicita Luigi Donato Concetta Scimone Carmela Rinaldi Rosalia D’Angelo Antonina Sidoti Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes
description	Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene <i>FMO3</i>, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The <i>FMO3</i> screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of <i>FMO3</i>, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of <i>FMO3</i> variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis.
format	article
author	Simona Alibrandi Fabiana Nicita Luigi Donato Concetta Scimone Carmela Rinaldi Rosalia D’Angelo Antonina Sidoti
author_facet	Simona Alibrandi Fabiana Nicita Luigi Donato Concetta Scimone Carmela Rinaldi Rosalia D’Angelo Antonina Sidoti
author_sort	Simona Alibrandi
title	Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes
title_short	Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes
title_full	Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes
title_fullStr	Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes
title_full_unstemmed	Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes
title_sort	adaptive modelling of mutated fmo3 enzyme could unveil unexplored scenarios linking variant haplotypes to tmau phenotypes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b47719394e884891aed29167725e8868
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Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes

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