Investigating the contribution of the telomeric gene AKTIP in progeroid syndromes with unknown mutations

Some progeroid syndromes have been linked to lamins and to DNA and telomere metabolism genes. However, in other progeroid disorders a causative gene mutation has not been identified. These different genetic situations converge into a common phenotype that includes senescence, heterochromatin alterations, DNA damage and telomere aberrations. At the organismal level, the progeroid phenotype is characterized by premature aging, including bone and skin defects that have been related to stem cell dysfunction. We have described a human protein named AKTIP (Ft1 in mouse and peo in Drosophila), which is involved in processes leading to progeria. AKTIP is located at the nuclear periphery and binds lamins. Its depletion in human primary fibroblasts causes senescence, DNA damage and heterochromatin alterations. AKTIP controls telomere metabolism and is related to DNA replication. We generated Ft1-depleted mice, which display skin and bone phenotypes. We propose here to study AKTIP as a part of a lamina-connected multimeric complex playing a role in topologically challenging DNA replication. We postulate that this hub could be the unifying effector trait of different genetic mutations underpinning progeroid disorders. We propose to develop this idea by defining whether in neglected progeroid samples AKTIP is mutated. Along with this, we plan to define the AKTIP interactome by mass spectrometry, in tube analysis and high-resolution microscopy in wild type and progeroid cells, from classical and neglected progerias. In Ft1-depleted mice, we will study skin and bone progenitor cells to investigate the implication of the hub in the multi-organ nature of progeroid organismal pathophysiology. We expect that this study will give insights for a unifying view of the biomolecular determinants of progerias, both classical and neglected cases, at the cell and organismal level, and new information on the implication of the nuclear lamina and of AKTIP in complex DNA metabolism