Title The Pathogenicity of Tafazzin Variants and their Implications in Barth Syndrome: A Bioinformatics Analysis Title (croatian) Patogeneza varijanti tafazina u Barthovom sindromu: bioinformatička analiza Author Irma Markesina Mentor Christian Andrew Reynolds (mentor)Mentor Gordana Apic (komentor) Committee member Christian Andrew Reynolds (član povjerenstva)Committee member Toni Todorovski (predsjednik povjerenstva)Committee member Dean Marković (član povjerenstva)Granter University of Rijeka Defense date and country 2023-09-27, Croatia Scientific / art field, BIOTECHNICAL SCIENCES Abstract Barth syndrome (BTHS) is an X-linked genetic disease characterized by severe cardiovascular defects, skeletal muscle weakness and neutropenia. Defects in the protein tafazzin, which is encoded by the TAZ gene, have been identified to give rise to BTHS through impaired capability of remodeling the mitochondrial phospholipid cardiolipin (CL). Even though the genetic defects responsible for the disease are known, the links between specific TAZ mutation variants and mechanisms of BTHS pathogenicity
... More haven't been thoroughly examined. The aim of this work was to present bioinformatics methods which would facilitate this type of research and, using these methods, examine tafazzin protein features, map all known benign and pathogenic tafazzin protein changes to its corresponding domains, identify the mutations that are found in evolutionarily conserved regions, and highlight potentially important domains and mutations for future in silico and in vivo research. The variants were compiled from the Barth Syndrome Foundation's Tafazzin Human Variants Database. Databases UniProt, ClinVar, OMIM and GnomAD were used in addition. Seven pathogenicity prediction softwares were used to analyze potential pathogenicity of missense variants based on protein structure and evolutionary conservation. A species alignment analysis was done using ClustalOmega. Our results show that tafazzin is not subject to binding CL via induced-fit, but that the interaction is rather based on conformational selection, indicating a potential conformational flexibility that might enable interactions with diverse phospholipids without significant structural changes caused by ligand binding. We hypothesize that tafazzin's conformational flexibility may be influenced by the surrounding microenvironment, including membrane composition and neighboring molecules. We demonstrate pathogenic mutational enrichment in five of the protein's domains and show that 34 out of 62 pathogenic missense variants are predicted to be detrimental to the protein's function. Through further refinement, we show that two domains of the protein, HX4D and MT1, are highlighted as significantly enriched in pathogenic variants. D74 and D75 mutations in the HX4D domain and R94 mutations in the MT1 domain, identified as pathogenic through our methods, suggest the likelihood of interactions between these domains due to the complementary charges of aspartate and arginine, hinting at a potential active site. Finally, we discuss the potential of studying these two domains and TAZ mutation variants in general by applying molecular dynamics simulations and using the model organism Saccharomyces cerevisiae. Less Abstract (croatian) Barthov sindrom (BTHS) je X-vezana genetska bolest karakterizirana teškim kardiovaskularnim defektima, slabošću skeletnih mišića i neutropenijom. Defekti u proteinu tafazinu kodiranom sa strane TAZ gena identificirani su kao uzrok BTHS-a, djelujući pogubno na sposobnost remodeliranja mitohondrijskog fosfolipida kardiolipina (CL). Iako su genetski poremećaji odgovorni za bolest poznati, poveznice između specifičnih TAZ varijanti i mehanizama BTHS patogenosti nisu detaljno istražene. Cilj ovog
... More rada bio je predstaviti bioinformatičke metode koje bi omogućile takvo istraživanje, te pomoću njih proučiti proteinske značajke tafazina, mapirati sve do sada poznate benigne i patogene promjene proteina na njegove domene, identificirati mutacije koje se nalaze na evolucijski konzerviranim mjestima proteina, te istaknuti potencijalno važne domene i mutacije za buduća in silico i in vivo istraživanja. Varijante u ovom radu su primarno kompilirane iz Barth syndrome foundation baze podataka Tafazzin Human Variants, a potom su korištene i baze podataka UniProt, ClinVar, OMIM i GnomAD. Sedam programa za predviđanje patogenosti korišteno je u svrhu analize patogenosti missense varijanti tafazina na temelju proteinske strukture i evolucijske konzervacije. Analiza poravnanja proteinskih sekvenci između vrsti napravljena je pomoću programa ClustalOmega. Predstavljamo rezultate koji ukazuju na to da tafazin ne podliježe vezanju CL-a putem inducirane prilagodbe, već konformacijske selekcije, te da stoga postoji potencijalna konformacijska fleksibilnost proteina koja omogućuje interakcije s raznim fosfolipidima bez značajnih strukturalnih promjena uzrokovanih vezanjem liganada. Prilažemo hipotezu da konformacijska fleksibilnost tafazina podliježe utjecaju mikrookoliša, uključujući kompoziciju membrane i susjedne molekule. Pokazujemo patogeno obogaćenje u pet domena tafazina, te da su 34 od 62 patogene missense varijante predviđene kao pogubne za funkciju proteina. Izdvajamo dvije domene tafazina, HX4D i MT1, kao značajno obogaćene patogenim varijantama. Identificirane kao patogene pomoću naših metoda, D74 i D75 mutacije u HX4D domeni, te R94 mutacije u MT1 domeni sugeriraju na mogućnost interakcija između ove dvije domene zbog komplementarnih naboja aspartata i arginina, što potencijalno ukazuje i na aktivno mjesto proteina. Naposlijetku, raspravljamo o potencijalu izučavanja ove dvije domene i TAZ mutacijskih varijanti pomoću metoda kao što su simulacije molekularne dinamike i korištenje modelnog organizma Saccharomyces cerevisiae. Less Keywords
tafazzin
TAZ
Barth syndrome
BTHS
bioinformatics
in silico
mutations
variants
enrichment
domains
conservation
Keywords (croatian)
tafazin
TAZ
Barthov sindrom
BTHS
bioinformatika
in silico
mutacije
varijante
obogaćenje
domene
konzervacija
Language english URN:NBN urn:nbn:hr:193:926005 Study programme Title: Biotechnology in medicine Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2023-09-27 16:38:55
