Disease-related versus polymorphic mutations in human mitochondrial tRNAs - Where is the difference?

A number of point mutations in human mitochondrial (mt) tRNA genes are corr elated with a variety of neuromuscular and other severe disorders including encephalopathies, myopathies, cardiopathies and diabetes. The complexity o f the genotype/phenotype relationships, the diversity of possible molecular impacts of the different mutations at the tRNA structure/function levels, and the exponential discovery of new mutations call for the search for unif ying features. Here, the basic features (at the levels of primary and secon dary structure) of 68 'pathogenic' mutations are compared with those of 64 'polymorphic' neutral mutations, revealing that these standard parameters f or mutant analysis are not sufficient to predict the pathogenicity of mt tR NA mutations. Thus, case by case molecular investigation remains the only m eans of assessing the growing family of pathogenic mutations in mt tRNAs. N ew lines of research are suggested.