Molecular genetics of mitochondrial disorders

Mitochondrial respiratory chain (RC) disorders (RCDs) are a group of genetically and clinically heterogeneous diseases because of the fact that protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure, and function of mitochondria, including DNA replication, transcription, and translation, all require nuclear-encoded genes. In this review, primary molecular defects in the mitochondrial genome and major classes of nuclear genes causing mitochondrial RCDs, including genes underlying mitochondrial DNA (mtDNA) depletion syndrome, as well as genes encoding RC subunits, complex assembly genes, and translation factors, are described. Diagnostic methodologies used to detect common point mutations, large deletions, and unknown point mutations in the mtDNA and to quantify mutation heteroplasmy are also discussed. Finally, the selection of nuclear genes for gold standard sequence analysis, application of novel technologies including oligonucleotide array comparative genomic hybridization, and massive parallel sequencing of target genes are reviewed. © © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:154–162.