Figure 1. Human Disease-Associated Mutations in Genes Involved in mtDNA Replication and Maintenance.

Mutations reported in POLG [36,151–162], TWINKLE (gene also known as PEO1) [34,38,39,163–167], and ANT1 (gene also known as SLC25A4) [35,40] proteins associated with human diseases.

Mutations in black are associated with PEO, those in blue are associated with Alpers syndrome, red indicates mutations present in both PEO and Alpers, and green indicates mutations associated with other disorders. Italics indicate changes in DNA sequence.

A) POLG. The light green and light blue segments represent the exonuclease and polymerase domains, respectively. Highly conserved motifs within each are shown as red segments. The POLG mutation figure is adapted from the Human DNA Polymerase Gamma Mutation Database maintained by the Mitochondrial Replication Group at the National Institute of Environmental Health Sciences (http://dir-apps.niehs.nih.gov/polg).

B) TWINKLE. The pink domain is the primase-helicase linker region, as identified by homology to T7 phage protein [34].

C) ANT1. In addition to the pathogenic mutations shown within the protein, a 3.3-kb deletion upstream of ANT1 results in derepression of ANT1 and is associated with facioscapulohumeral muscular dystrophy [168].

Dup, duplication; fs, frameshift mutation; ins, insertion; *, termination codon