De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome.

Mutations in POLG are a major contributor to pediatric and adult mitochondrial diseases. However, the consequences of many POLG mutations are not well understood. We investigated the molecular cause of Alpers syndome in a patient harboring the POLG mutations A467T in trans with c.2157+5_+6 gc-->ag in intron 12. Analysis of transcripts arising from the c.2157+5_+6 gc-->ag allele revealed alternative splicing with an insertion of 30 intronic nucleotides leading to a premature termination codon. These transcripts were subsequently removed through nonsense-mediated decay, leading to haplotype insufficiency due to expression of the A467T allele and decreased expression of the c.2157+5_+6 gc-->ag allele, which is likely responsible for the Alpers syndrome phenotype.