New genes involved in mitochondrial and neurodegenerative diseases identified by whole exome sequencing

The scope of my thesis was the identification of genes responsible for: 1) an adult-onset neurological syndrome, with leukodystrophy and motor-neuron disease, in two half-siblings; 2) an infantile hypertrophic cardiomyopathy with lactic acidosis and mitochondrial respiratory chain defects. Since all genetic screenings performed on the basis of clinical manifestations did not provide a diagnosis for these patients, we carried out whole exome sequencing. My work contributed to the publications of three papers. In the second chapter of this thesis, there is the article concerning the identification and characterization of the first GFAP-ε mutation,causing an adult form of Alexander disease in two affected siblings. The male presented a severe motor-neuron disease whereas his sister showed a mild movement disorder with cognitive impairment. In addition to the GFAP-ε mutation, we found a variant in HDAC6 on chromosome X, present only in the male patient; HDAC6 is a candidate MND susceptibility gene and the identified missense variant is probably responsible for his different phenotype. Cellular models were used to experimentally prove the altered functionality of mutant GFAP-ε and HDAC6. The third chapter contains the paper reporting the first mutations in MTO1, responsible for a mitochondrial disorder associated with hypertrophic cardiomyopathy, lactic acidosis and mitochondrial respiratory chain defects. Then chapter four consists of the article where we described and characterized news MTO1 mutations found in other patients. In both articles characterization of the identified mutations and validation of their deleterious effects were assessed in patients’ specimens (fibroblasts) and in yeast Saccharomyces cerevisiae.