MITMED: A MULTICENTER CONSORTIUM FOR THE IDENTIFICATION AND CHARACTERIZATION OF NUCLEAR GENES RESPONSIBLE FOR HUMAN MITOCHONDRIAL DISORDERS

The aim of the research

Main researcher

MASSIMO ZEVIANI

Partners

RODOLFO COSTA

The tremendous clinical, biochemical and molecular heterogeneity of mitochondrial disorders makes virtually each member of the whole mitochondrial proteome a candidate for disease.

As a result, only 40% of adult-onset disorders are currently diagnosed at the molecular level, and much lesser so in infantile syndromes. However, new technological and biocomputational tools offer the possibility of rapid and affordable analysis of the exome, i.e. the coding regions of all genes in single individuals or small families. Mitochondrial disease proteins can then be selected by exploiting predictive softwares, dedicated databases, and ex vivo experiments. MitMed is a Telethon Consortium dedicated to (i) the identification of mitochondrial disease genes and their characterization using (ii) in vitro analysis of disease proteins and (iii) creation and investigation of in vivo disease models. MitMed activities will be grouped in three Workpackages (WP). In WP1, MitMed will carry out mitochondrial disease gene hunting using exome sequencing in a large cohort of selected mitochondrial disease patients. MitMed WP2 will address the in vitro analysis of several disease gene products identified during the Telethon GGP07019 project lifetime, of which MitMed is the logical continuation. A powerful tool for the identification of proteins, called mass-spectrometry, will be applied to dissect out the partner proteins interacting with Mpv17, responsible of hepatocerebral mtDNA depletion, of its yeast ortholog Sym1, and of TTC19, a putative assembly factor of complex III whose absence causes cIII-defective, progressive neurodegeneration. MitMed WP3 will address the creation of and investigation on in vivo models, namely, knockout mice and flies for Mpv17 and TTC19; a knockout zebrafish for Mpv17; and yeast mutant strains for Mpv17/Sym1 and for SDHAF1, a complex II (cII) assembly factor that is mutated in cII-defective severe leukoencephalopathy. Any new gene identified in WP1 will then be characterized in WP2 and WP3 during the MitMed lifetime. Whenever possible, the results of the MitMed project will directly feed the activity of MitCare, a Telethon program project dedicated to the development of experimental therapy for mitochondrial disorders.

Scientific publications

2015 NUCLEIC ACIDS RESEARCH
Nucleotide excision repair efficiency in quiescent human fibroblasts is modulated by circadian clock
Bee, L; Marini, S; Pontarin, G; Ferraro, P; Costa, R; Albrecht, U; Celotti, LCites: 2 (*)
2015 AMERICAN JOURNAL OF HUMAN GENETICS
TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies
Powell CA, Kopajtich R, D'Souza AR, Rorbach J, Kremer LS, Husain RA, Dallabona C, Donnini C, Alston CL, Griffin H, Pyle A, Chinnery PF, Strom TM, Meitinger T, Rodenburg RJ, Schottmann G, Schuelke M, Romain N, Haller RG, Ferrero I, Haack TB, Taylor RW, Prokisch H, Minczuk MCites: 1 (*)
2015 BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
Emerging concepts in the therapy of mitochondrial disease
Viscomi, C; Bottani, E; Zeviani, MCites: 6 (*)
2015 AMERICAN JOURNAL OF HUMAN GENETICS
COQ4 Mutations Cause a Broad Spectrum of Mitochondrial Disorders Associated with CoQ(10) Deficiency
Brea-Calvo, G; Haack, TB; Karall, D; Ohtake, A; Invernizzi, F; Carrozzo, R; Kremer, L; Dusi, S; Fauth, C; Scholl-Burgi, S; Graf, E; Ahting, U; Resta, N; Laforgia, N; Verrigni, D; Okazaki, Y; Kohda, M; Martinelli, D; Freisinger, P; Strom, TM; Meitinger, T;Cites: 9 (*)
2015 CELL METABOLISM
Opa1 Overexpression Ameliorates the Phenotype of Two Mitochondrial Disease Mouse Models
Civiletto, G; Varanita, T; Cerutti, R; Gorletta, T; Barbaro, S; Marchet, S; Lamperti, C; Viscomi, C; Scorrano, L; Zeviani, MCites: 16 (*)
2015 AMERICAN JOURNAL OF HUMAN GENETICS
RNASEH1 Mutations Impair mtDNA Replication and Cause Adult-Onset Mitochondrial Encephalomyopathy
Reyes, A; Melchionda, L; Nasca, A; Carrara, F; Lamantea, E; Zanolini, A; Lamperti, C; Fang, MY; Zhang, JG; Ronchi, D; Bonato, S; Fagiolari, G; Moggio, M; Ghezzi, D; Zeviani, MCites: 2 (*)
2014 NEUROLOGY
Novel (ovario) leukodystrophy related to AARS2 mutations
Dallabona, C; Diodato, D; Kevelam, SH; Haack, TB; Wong, LJ; Salomons, GS; Baruffini, E; Melchionda, L; Mariotti, C; Strom, TM; Meitinger, T; Prokisch, H; Chapman, K; Colley, A; Rocha, H; Ounap, K; Schiffmann, R; Salsano, E; Savoiardo, M; Hamilton, EM; AbbCites: 4 (*)
2014 EMBO REPORTS
UCP4C mediates uncoupled respiration in larvae of Drosophila melanogaster
Da-Re, C; De Pitta, C; Zordan, MA; Teza, G; Nestola, F; Zeviani, M; Costa, R; Bernardi, PCites: 1 (*)
2014 MOLECULAR THERAPY
Gene Therapy Using a Liver-targeted AAV Vector Restores Nucleoside and Nucleotide Homeostasis in a Murine Model of MNGIE
Torres-Torronteras, J; Viscomi, C; Cabrera-Perez, R; Camara, Y; Di Meo, I; Barquinero, J; Auricchio, A; Pizzorno, G; Hirano, M; Zeviani, M; Marti, RCites: 3 (*)
2014 JOURNAL OF BIOLOGICAL CHEMISTRY
Functional Characterization of drim2, the Drosophila melanogaster Homolog of the Yeast Mitochondrial Deoxynucleotide Transporter
Da-Re, C; Franzolin, E; Biscontin, A; Piazzesi, A; Pacchioni, B; Gagliani, MC; Mazzotta, G; Tacchetti, C; Zordan, MA; Zeviani, M; Bernardi, P; Bianchi, V; De Pitta, C; Costa, RCites: 2 (*)
2014 HUMAN MUTATION
VARS2 and TARS2 Mutations in Patients with Mitochondrial Encephalomyopathies
Diodato, D; Melchionda, L; Haack, TB; Dallabona, C; Baruffini, E; Donnini, C; Granata, T; Ragona, F; Balestri, P; Margollicci, M; Lamantea, E; Nasca, A; Powell, CA; Minczuk, M; Strom, TM; Meitinger, T; Prokisch, H; Lamperti, C; Zeviani, M; Ghezzi, DCites: 2 (*)
2014 MOLECULAR THERAPY
AAV-mediated Liver-specific MPV17 Expression Restores mtDNA Levels and Prevents Diet-induced Liver Failure
Bottani, E; Giordano, C; Civiletto, G; Di Meo, I; Auricchio, A; Ciusani, E; Marchet, S; Lamperti, C; d'Amati, G; Viscomi, C; Zeviani, MCites: 1 (*)
2014 NATURE COMMUNICATIONS
EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia
Boczonadi, V; Muller, JS; Pyle, A; Munkley, J; Dor, T; Quartararo, J; Ferrero, I; Karcagi, V; Giunta, M; Polvikoski, T; Birchall, D; Princzinger, A; Cinnamon, Y; Lutzkendorf, S; Piko, H; Reza, M; Florez, L; Santibanez-Koref, M; Griffin, H; Schuelke, M; Elpeleg, O; Kalaydjieva, L; Lochmuller, H; Elliott, DJ; Chinnery, PF; Edvardson, S; Horvath, RCites: 2 (*)
2014 JOURNAL OF BIOLOGICAL CHEMISTRY
Leigh Syndrome in Drosophila melanogaster
Da-Rè C; von Stockum S; Biscontin A; Millino C; Cisotto P; Zordan A; Zeviani M; Bernardi P; De Pittà C; Costa RCites: 1 (*)
2013 HUMAN MUTATION
A Homozygous Mutation in LYRM7/MZM1L Associated with Early Onset Encephalopathy, Lactic Acidosis, and Severe Reduction of Mitochondrial Complex III Activity
Invernizzi, F; Tigano, M; Dallabona, C; Donnini, C; Ferrero, I; Cremonte, M; Ghezzi, D; Lamperti, C; Zeviani, MCites: 2 (*)
2013 AMERICAN JOURNAL OF HUMAN GENETICS
ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy
Haack, TB; Kopajtich, R; Freisinger, P; Wieland, T; Rorbach, J; Nicholls, TJ; Baruffini, E; Walther, A; Danhauser, K; Zimmermann, FA; Husain, RA; Schum, J; Mundy, H; Ferrero, I; Strom, TM; Meitinger, T; Taylor, RW; Minczuk, M; Mayr, JA; Prokisch, HCites: 11 (*)
2013 LANCET NEUROLOGY
Peripheral neuropathy in mitochondrial disorders
Pareyson, D; Piscosquito, G; Moroni, I; Salsano, E; Zeviani, MCites: 5 (*)
2013 ORPHANET JOURNAL OF RARE DISEASES
Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant
Melchionda, L; Fang, MY; Wang, HR; Fugnanesi, V; Morbin, M; Liu, XZ; Li, WY; Ceccherini, I; Farina, L; Savoiardo, M; DAdamo, P; Zhang, JG; Costa, A; Ravaglia, S; Ghezzi, D; Zeviani, MCites: 2 (*)
2013 HUMAN MUTATION
MTO1 Mutations are Associated with Hypertrophic Cardiomyopathy and Lactic Acidosis and Cause Respiratory Chain Deficiency in Humans and Yeast
Baruffini, E; Dallabona, C; Invernizzi, F; Yarham, JW; Melchionda, L; Blakely, EL; Lamantea, E; Donnini, C; Santra, S; Vijayaraghavan, S; Roper, HP; Burlina, A; Kopajtich, R; Walther, A; Strom, TM; Haack, TB; Prokisch, H; Taylor, RW; Ferrero, I; Zeviani, M; Ghezzi, DCites: 7 (*)
2012 JOURNAL OF MEDICAL GENETICS
Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency
Alston, CL; Davison, JE; Meloni, F; van der Westhuizen, FH; He, LP; Hornig-Do, HT; Peet, AC; Gissen, P; Goffrini, P; Ferrero, I; Wassmer, E; McFarland, R; Taylor, RWCites: 10 (*)
2012 NEUROMUSCULAR DISORDERS
MELAS-like encephalomyopathy caused by a new pathogenic mutation in the mitochondrial DNA encoded cytochrome c oxidase subunit I
Lamperti, C; Diodato, D; Lamantea, E; Carrara, F; Ghezzi, D; Mereghetti, P; Rizzi, R; Zeviani, MCites: 1 (*)
2012 AMERICAN JOURNAL OF HUMAN GENETICS
Cowchock Syndrome Is Associated with a Mutation in Apoptosis-Inducing Factor
Rinaldi, C; Grunseich, C; Sevrioukova, IF; Schindler, A; Horkayne-Szakaly, I; Lamperti, C; Landoure, G; Kennerson, ML; Burnett, BG; Bonnemann, C; Biesecker, LG; Ghezzi, D; Zeviani, M; Fischbeck, KHCites: 14 (*)
2012 AMERICAN JOURNAL OF HUMAN GENETICS
Mutations of the Mitochondrial-tRNA Modifier MTO1 Cause Hypertrophic Cardiomyopathy and Lactic Acidosis
Ghezzi, D; Baruffini, E; Haack, TB; Invernizzi, F; Melchionda, L; Dallabona, C; Strom, TM; Parini, R; Burlina, AB; Meitinger, T; Prokisch, H; Ferrero, I; Zeviani, MCites: 39 (*)
2012 AMERICAN JOURNAL OF HUMAN GENETICS
Lack of the Mitochondrial Protein Acylglycerol Kinase Causes Sengers Syndrome
Mayr, JA;Haack, TB;Graf, E;Zimmermann, FA;Wieland, T;Haberberger, B;Superti-Furga, A;Kirschner, J;Steinmann, B;Baumgartner, MR;Moroni, I;Lamantea, E;Zeviani, M;Rodenburg, RJ;Smeitink, J;Strom, TM;Meitinger, T;Sperl, W;Prokisch, HCites: 42 (*)
2012 EMBO MOLECULAR MEDICINE
Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy
Di Meo, I; Auricchio, A; Lamperti, C; Burlina, A; Viscomi, C; Zeviani, MCites: 9 (*)
2012 AMERICAN JOURNAL OF HUMAN GENETICS
Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease
Indrieri, A; van Randen, VA; Tiranti, V; Morleo, M; Iaconis, D; Tammaro, R; DAmato, I; Conte, I; Maystadt, I; Demuth, S; Zvulunov, A; Kutsche, K; Zeviani, M; Franco, BCites: 20 (*)
2012 JOURNAL OF MEDICAL GENETICS
Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing
Haack, TB; Haberberger, B; Frisch, EM; Wieland, T; Iuso, A; Gorza, M; Strecker, V; Graf, E; Mayr, JA; Herberg, U; Hennermann, JB; Klopstock, T; Kuhn, KA; Ahting, U; Sperl, W; Wilichowski, E; Hoffmann, GF; Tesarova, M; Hansikova, H; Zeman, J; Plecko, B; Zeviani, M; Wittig, I; Strom, TM; Schuelke, M; Freisinger, P; Meitinger, T; Prokisch, HCites: 35 (*)
2012 BRAIN
Leukoencephalopathy with thalamus and brainstem involvement and high lactate LTBL caused by EARS2 mutations
Steenweg, ME; Ghezzi, D; Haack, T; Abbink, TEM; Martinelli, D; van Berkel, CGM; Bley, A; Diogo, L; Grillo, E; Naude, JTW; Strom, TM; Bertini, E; Prokisch, H; van der Knaap, MS; Zeviani, MCites: 50 (*)
2012 MOLECULAR GENETICS AND METABOLISM
A novel homozygous mutation in SUCLA2 gene identified by exome sequencing
Lamperti, C; Fang, MY; Invernizzi, F; Liu, XZ; Wang, HR; Zhang, Q; Carrara, F; Moroni, I; Zeviani, M; Zhang, JG; Ghezzi, DCites: 13 (*)