MITMED CONSORTIUM: FROM THE IDENTIFICATION AND CHARACTERIZATION OF NUCLEAR GENES RESPONSIBLE FOR HUMAN MITOCHONDRIAL DISORDERS TOWARDS POTENTIAL THERAPEUTIC APPROACHES IN EXPERIMENTAL MODELS

The aim of the research

Main researcher

DANIELE GHEZZI

Partners

RODOLFO COSTA

The genetic cause of mitochondrial disorders (MD) includes mutations in either mitochondrial DNA (mtDNA) or nuclear DNA genes.

The broad genetic heterogeneity of MD is a problem not only to identify new responsible genes, but also to achieve molecular diagnosis by screening known disease genes. For this reason, the genetic defect remains unknown in a large fraction of patients with MD. For this project (MidMed), we will use Next Generation Sequencing (NGS) approaches to identify new disease-genes and to improve genetic diagnosis in our cohort of MD patients. As part of the previous GPP11011 project, by NGS in two subjects we have recently identified variants predicted to be deleterious in two nuclear genes not previously associated with MD; we are currently investigating them in patients' cells and we will better characterize the corresponding proteins using in vitro analyses. Moreover, any new gene identified will then be studied during the present MitMed lifetime. Yeast, fly and zebrafish models mimicking mutations in MPV17, responsible of hepatocerebral mtDNA depletion in humans, have been created and will be further characterize to gain insight on mechanism of disease. Additional models for APOPT1, mutations of which we have recently published as cause of mitochondrial leukoencephalopathy, or for newly identified genes will be exploited. Finally, we will look at drugs or supplements which have positive properties on mitochondrial functioning, either in specific genetic conditions or as generalized effect. From a preliminary screening in a definite yeast model (POLG mutant strains) we have already identified 6 molecules that will be extensively tested using the available experimental models or mutant cells from patients. We want to obtain a translational impact from the work done and the knowledge reached in the last years, improving the percentages of MD individuals with genetic diagnosis, and testing potential pharmacological approaches.

Scientific publications

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 (*)