Molecular characterization of disease-linked polynucleotide phosphorylase variants (POLYVAR)

Polynucleotide phosphorylase (PNPase) is a protein conserved from bacteria to humans. In humans, PNPase is localized within the mitochondria, which are organelles playing the fundamental role of providing energy to the cells. It has recently been discovered that mutations in the PNPase encoding gene that cause amino acid changes in the protein, are the source of family diseases with a very variable spectrum of severity and symptoms, ranging from deafness with adult onset to very serious multisystem diseases leading to death in early childhood. Although the heterogeneity of clinical manifestations is a common feature of diseases due to mitochondrial malfunction, diverse defects at the molecular level in PNPase pathological variants could also contribute to this heterogeneity. This project aims to study the activity of some PNPase variants identified in patients with different diseases in order to correlate, if possible, the PNPase molecular defects caused by different mutation with the severity of the pathological conditions that occur in the patients.

This project is important because it will provide a better understanding of the molecular mechanisms underlying PNPase-dependent diseases, which are currently poorly understood. It will also allow the development of assays and models that can be applied to the characterization of other already known or new pathological variants of PNPase.