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Genetic bases and experimental models for the study of inherited metabolic diseases

Inherited metabolic diseases are genetic disorders caused by the alteration of a specific metabolic reaction. We focused on the study of the genetic bases of two main types of metabolic disorders, mitochondrial diseases and urea cycle defects. In this work, we report the characterization of novel genes that are potentially involved in mitochondrial respiratory chain defects: we identified three novel COX-assembly genes required for Cytochrome c Oxidase (COX) biogenesis and two novel genes involved in coenzyme Q biosynthesis.These genes represent new candidates to be screened in patients with isolated COX defect or primary coenzyme Q deficiency, without mutations in other known genes. We then studied a family affected by coenzyme Q deficiency and found a homozygous mutation in the COQ2 gene, this is the first report of a mutation in a ubiquinone biosynthetic gene. Moreover, we developed a C.elegans model of COX defect in order to study the pathogenesis of this disease. Finally, we performed a mutational screening in a cohort of patients affected by argininosuccininc aciduria and developed a functional complementation assay using S.cerevisiae strain to prove the pathogenesis of the novel mutations; we also established some genotype-phenotype correlations.