title: Novel mutation in mitochondrial Elongation Factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation.
abstract: The mitochondrial Elongation Factor Tu (EF-Tu), encoded by the TUFM gene, is a highly conserved GTPase, which is part of the mitochondrial protein translation machinery. In its activated form it delivers the aminoacyl-tRNAs to the A site of the mitochondrial ribosome. We report here on a baby girl with severe infantile macrocystic leukodystrophy with micropolygyria and a combined defect of complexes I and IV in muscle biopsy, caused by a novel mutation identified in TUFM. Using human mutant cells and the yeast model, we demonstrate the pathological role of the novel variant. Moreover, results of a molecular modeling study suggest that the mutant is inactive in mitochondrial polypeptide chain elongation, probably as a consequence of its reduced ability to bind mitochondrial aa-tRNAs. Four patients have so far been described with mutations in TUFM, and, following the first description of the disease in a single patient, we describe similar clinical and neuroradiological features in an additional patient.
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Di Nottia
authors.affiliation: Pasteur Institute Italy - Cenci Bolognetti Foundation, Italy; Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Montanari
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Verrigni
authors.affiliation: Department of Sciences and Technologies, University Parthenope of Naples, Centro Direzionale Isola C4, I-80143 Naples, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Oliva
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Torraco
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge, UK.
authors.forename: Erika
authors.initials: E
authors.lastname: Fernandez-Vizarra
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Diodato
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rizza
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Catteruccia
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.affiliation: Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Francisci
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: rosalba.carrozzo@opbg.net.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
mesh_terms: D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D010441:Peptide Chain Elongation, Translational; D010444:Peptide Elongation Factor Tu / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C091648:TUFM protein, human; D010444:Peptide Elongation Factor Tu
keywords: Leukodystrophy; Mitochondrial translation; OXPHOS defects; TUFM