Nuclear gene defects in respiratory chain disorders

Deficiencies in the activity of the components of the mitochondrial respira tory chain can result from mutations in genes encoded in the mitochondrial (mtDNA) or nuclear genomes. Mutations in mtDNA have been identified over th e past decade in a wide spectrum of clinical disorders, and attention has n ow turned to identifying nuclear gene defects. Positional cloning, candidat e gene analysis, and functional complementation in patient cell lines have all been used with success. Mutations in gene coding for structural subunit s of the respiratory chain complexes appear to be less numerous than defect s in genes associated with some aspect of the biogenesis of the respiratory chain. Despite the fact that many of the nuclear disease genes so far iden tified are ubiquitously expressed, tissue specificity of the biochemical an d clinical phenotype is the rule rather than the exception. This selective vulnerability of different cell populations remains unexplained. The majori ty of patients with a biochemical deficiency in one or the other of the res piratory chain complexes do not yet have a molecular diagnosis.