Fig. 6.

Heterozygous POLG mutations. Panel A, model of the catalytic subunit of POLG illustrating mutations that have been reported to be heterozygous in the POLG Pathogenicity Prediction Server database. Mutations for which substantial corroborative evidence indicates dominant inheritance are shown in red spheres, and surround the polymerase active site (black arrow). Yellow spheres indicate mutations for which there is insufficient data to argue dominant status. Green spheres depict mutations least likely to be dominant. The color status is not indicative with respect to pathogenicity in compound heterozygous form. Two of the most common pathogenic POLG mutations, p.A467T and p.W748S, are shown in cyan spheres. Panel B, close-up of the active site of the polymerase domain of POLGA (black arrow). The putatively-dominant mutant residues (red spheres) interact with the incoming dNTP (orange), template DNA or the catalytic Mg-ions (black spheres). A hotspot for these is on the O-helix, in which every residue facing the polymerase active site has been reported in a heterozygous POLG patient. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)