Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca2+

摘要: Mutations in C19orf12 have been identified patients affected by Neurodegeneration with Brain Iron Accumulation (NBIA), a clinical entity characterized iron accumulation the basal ganglia. By using western blot analysis specific antibody and confocal studies, we showed that wild-type protein was not exclusively present mitochondria, but also Endoplasmic Reticulum (ER) MAM (Mitochondria Associated Membrane), while mutant variants presented different localization. Moreover, after induction of oxidative stress, GFP-tagged able to relocate cytosol. On contrary, isoforms were respond stress. High mitochondrial calcium concentration increased H2O2 induced apoptosis found fibroblasts derived from one patient as compared controls. is 17 kDa membrane-associated whose function still unknown. Our silico investigation suggests that, glycine zipper motifs form helical regions spanning membrane. The N- C-terminal respect transmembrane portion, on are predicted rearrange structural domain, which homologs N-terminal regulatory domain magnesium transporter MgtE, suggesting may act for human MgtE transporters. mutations here described affect respectively residue motifs, involved dimerization helices impair correct localization into membranes, important protein-protein interaction.