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Mutations at the flavin binding site of ETF:QO yield a MADD-like severe phenotype in Drosophila
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Orientador(es)
Resumo(s)
Following 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 β-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
C12) 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 β-strand connected
by a short loop to an α-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.
Descrição
Palavras-chave
Flavoprotein MADD Doenças Genéticas
Contexto Educativo
Citação
Biochim Biophys Acta. 2012 Aug;1822(8):1284-92. Epub 2012 May 9