DO SEQUENCE VARIANTS IN THE MAJOR NONCODING REGION OF THE MITOCHONDRIAL GENOME INFLUENCE MITOCHONDRIAL MUTATIONS ASSOCIATED WITH DISEASE

Several different mutations in human mitochondrial DNA (mtDNA) have be en associated with disease, but their origins and the basis of the wid e phenotypic variability remain to be elucidated. We initially investi gated three patients with heteroplasmic disease associated mutations o f mtDNA for the presence of cis mutations in the major non-coding regi on that might influence their origins or pathology. A T-->C transition at nt 16189 previously identified in one patient with the 3243 G:C mu tation was associated with heteroplasmic length variation. Identical l ength variation was found in patient-derived cybrid lines containing 0 -97.5% 3243 G:C. Similarly, heteroplasmic length variation was demonst rated in 2/6 other probands with both the 3243 mutation and the 16189 polymorphism. The distribution of length variants in probands and in a symptomatic family members was identical in all cases. Thus length var iation appears to be independent of the level of 3243 mutant mtDNA and hence probably arose within both 3243 G:C and 3243 A:T mtDNAs. We sug gest that the 16189 polymorphism reflects a predisposition to the form ation or fixation of several different mutations in mitochondrial tRNA -(LeuUUR).