The np 3243 MELAS mutation: damned if you aminoacylate, damned if you don't

The np 3243 MELAS mtDNA mutation in tRNA(leu(UUR)) has been variously propo sed as a loss-of-function or as a gain-of-function mutation, based on appar ently contradictory studies in cultured cell lines, A new report describing the molecular effects of the mutation in vivo now mirrors this variability . This should prompt a more systematic reinvestigation of cells carrying th e mutation, in order to separate primary from secondary and pathogenic from compensatory effects, all of which may contribute to disease phenotype. Nu clear genetic and developmental background, mitochondrial haplotype, and ep igenetic effects may all influence the pathological outcome, Defects in bot h base-modification and aminoacylation of the mutant tRNA could play critic al roles.