Haplotype-matched controls as a tool to discriminate polymorphisms from pathogenic mutations in mtDNA

Abstract.

We have studied the pathogenic role of 10044A→G, a heteroplasmic mitochondrial DNA (mtDNA) mutation that has been suggested to be pathogenic in one family with severe pediatric morbidity. We found the mutation at an average frequency of 1.9% among 259 individuals including healthy controls. The mutation appeared to be heteroplasmic by restriction fragment analysis but analysis of subcloned polymerase chain reaction fragments confirmed homoplasmy. The polymorphic nature of 10044A→G was verified by demonstrating exclusive association with a rare mtDNA haplotype within haplogroup H. We suggest that the evaluation of putatively pathogenic mutations in mtDNA should include the analysis of a sufficient number of haplotype-matched control samples and that the heteroplasmy should be verified by cloning.