Phd in GENETICS AND MOLECULAR BIOLOGY

Thesis title: HUMAN INDUCED PLURIPOTENT STEM CELLS AS MODEL TO STUDY JOUBERT SYNDROME

Joubert syndrome (JS) is classified among recessive hereditary ataxias and is characterized by a peculiar cerebellar and brainstem malformation known as the “molar tooth sign” (MTS). To date, most of the identified causative genes of JS encode proteins involved in cilia function or assembly. We focused our attention on mutations in AHI1, the first gene to be associated to JS. In order to analyze how these mutations are involved in pathogenesis of JS, primary fibroblasts from two JS patients with different point mutations in AHI1 gene: c.2687A>G (p.His896Arg) and c.2168G>A (p.Arg723Gln) were used as cellular model in comparison with healthy donors. Our results show that: 1) AHI1 mutations affect ciliogenesis at morphological level; 2) AHI1 mutations affect cell cycle. In order to investigated the brain development, we reprogrammed fibroblasts in iPS cells and subsequently differentiate them in neurospheres and neuronal cells in order to investigate how the mutations in AHI1 gene could influence the formation and morphology of neurons, astrocytes and oligodendrocytes.