Alpers syndrome is an autosomal recessive mitochondrial DNA depletion disorder 
that affects children and young adults. It is characterized by a progressive, 
fatal brain and liver disease. This syndrome has been associated with mutations 
in POLG, the gene encoding the mitochondrial DNA polymerase (pol gamma). Most 
patients with Alpers syndrome have been found to be compound heterozygotes, 
carrying two pathogenic mutations in trans at the POLG locus. POLG is a 
nuclear-encoded gene whose protein product is imported into mitochondria, where 
it is essential for mtDNA replication and repair. We studied the skin 
fibroblasts of a patient with Alpers syndrome having the genotype 
E873stop/A467T. The E873stop mutation produces a premature termination codon 
(TAG) in exon 17. The A467T mutation produces a threonine to alanine 
substitution at a highly conserved site in exon 7. The allele bearing the stop 
codon (E873-TAG) is predicted to produce a truncated, catalytically inactive 
polymerase. However, only full-length pol gamma protein was detected by Western 
blot analysis. Here, we show that transcripts containing this stop codon undergo 
nonsense-associated alternative splicing and nonsense-mediated decay. More than 
95% of the functional POLG mRNA was derived from the allele bearing the A467T 
mutation and less than 5% contained the E873stop mutation. These events ensured 
that virtually all POLG protein in the cell was expressed from the A467T allele. 
Therefore, the Alpers phenotype in this patient was a consequence of a 
single-copy gene dose of the A467T allele, and selective elimination of 
transcripts bearing the E873stop mutation.