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Mutations at the flavin binding site of ETF:QO yield a MADD-like severe phenotype in Drosophila

2012-08Journal article Open access
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dc.contributor.authorJ. Gonçalves, Emanuel
dc.contributor.authorHenriques, Barbara J.
dc.contributor.authorRodrigues, Joao V.
dc.contributor.authorPrudencio, Pedro
dc.contributor.authorRocha, Hugo
dc.contributor.authorVilarinho, Laura
dc.contributor.authorMartinho, Rui Goncalo
dc.contributor.authorGomes, Claudio M.
dc.date.accessioned2018-12-07T14:52:41Z
dc.date.available2018-12-07T14:52:41Z
dc.date.issued2012-08
dc.description.abstractFollowing a screening on EMS-induced Drosophila mutants defective for formation and morphogenesis of epithelial cells, we have identified three lethal mutants defective for the production of embryonic cuticle. The mutants are allelic to the CG12140 gene, the fly homologue of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO). In humans, inherited defects in this inner membrane protein account for multiple acyl-CoA dehydrogenase deficiency (MADD), a metabolic disease of beta-oxidation, with a broad range of clinical phenotypes, varying from embryonic lethal to mild forms. The three mutant alleles carried distinct missense mutations in ETF:QO (G65E, A68V and S104F) and maternal mutant embryos for ETF:QO showed lethal morphogenetic defects and a significant induction of apoptosis following germ-band elongation. This phenotype is accompanied by an embryonic accumulation of short- and medium-chain acylcarnitines (C4. C8 and 02) as well as long-chain acylcarnitines (C14 and C16:1), whose elevation is also found in severe MADD forms in humans under intense metabolic decompensation. In agreement the ETF:QO activity in the mutant embryos is markedly decreased in relation to wild type activity. Amino acid sequence analysis and structural mapping into a molecular model of ETF:QO show that all mutations map at FAD interacting residues, two of which at the nucleotide-binding Rossmann fold. This structural domain is composed by a beta-strand connected by a short loop to an alpha-helix, and its perturbation results in impaired cofactor association via structural destabilisation and consequently enzymatic inactivation. This work thus pinpoints the molecular origins of a severe MADD-like phenotype in the fruit fly and establishes the proof of concept concerning the suitability of this organism as,a potential model organism for MADD. (C) 2012 Elsevier B.V. All rights reserved.
dc.description.sponsorshipFundacao para a Ciencia e Tecnologia (FCT/MCTES, Portugal) [PTDC/SAU-GMG/70033/2006, PTDC/QUI-BIQ/113027/2009, PTDC/BIA-BCM/111822/2009, PTDC/SAU-BID/111796/2009, SFRH/BPD/41609/2007, SFRH/BPD/74475/2010, SFRH/BPD/34763/2007]; CLIMB UK; [PEst-OE/EQB/LA0004/2011]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1016/j.bbadis.2012.05.003
dc.identifier.issn0925-4439
dc.identifier.urihttp://hdl.handle.net/10400.1/11166
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier Science Bv
dc.relationFunctional analysis and origins of the pathophysiology of mutations within genes of the fatty acid oxidation pathway: implications in the multiple acyl-CoA dehydrogenase deficiency disorder
dc.relationAnalysis of the role of N-terminal acetyltransferases during Drosophila development.
dc.relationCharacterization of mesenchymal to epithelial transition in Drosophila melanogaster
dc.relationDROSOPHILA AS A MODEL TO STUDY FATTY ACID METABOLIC DISORDERS
dc.relationPROTEIN FOLDING STUDIES AND ROLE OF POST-TRANSLATIONAL OXIDATIVE AND NITROSATIVE MODIFICATIONS IN HUMAN DISEASE
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectElectron-transfer flavoprotein
dc.subjectAcyl-coa dehydrogenase
dc.subjectFatty-acid oxidation
dc.subjectUbiquinone oxidoreductase
dc.subjectInborn-errors
dc.subjectCrystal-structures
dc.subjectPig-liver
dc.subjectDeficiency
dc.subjectProtein
dc.subjectSubstrate
dc.titleMutations at the flavin binding site of ETF:QO yield a MADD-like severe phenotype in Drosophila
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleFunctional analysis and origins of the pathophysiology of mutations within genes of the fatty acid oxidation pathway: implications in the multiple acyl-CoA dehydrogenase deficiency disorder
oaire.awardTitleAnalysis of the role of N-terminal acetyltransferases during Drosophila development.
oaire.awardTitleCharacterization of mesenchymal to epithelial transition in Drosophila melanogaster
oaire.awardTitleDROSOPHILA AS A MODEL TO STUDY FATTY ACID METABOLIC DISORDERS
oaire.awardTitlePROTEIN FOLDING STUDIES AND ROLE OF POST-TRANSLATIONAL OXIDATIVE AND NITROSATIVE MODIFICATIONS IN HUMAN DISEASE
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-GMG%2F70033%2F2006/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-BIQ%2F113027%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-BCM%2F111822%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-BID%2F111796%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F41609%2F2007/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F74475%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F34763%2F2007/PT
oaire.citation.endPage1292
oaire.citation.issue8
oaire.citation.startPage1284
oaire.citation.titleBiochimica et Biophysica Acta-Molecular Basis of Disease
oaire.citation.volume1822
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamSFRH
person.familyNameViegas Russo da Conceição Martinho
person.givenNameRui Gonçalo
person.identifier.ciencia-idF31D-C783-3D89
person.identifier.orcid0000-0002-1641-3403
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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