Do sequence variants in the major non-coding region of the mitochondrial genome influence mitochondrial mutations associated with disease?

Several different mutations in human mitochondrial DNA (mtDNA) have beenassociated with disease, but their origins and the basis of the widephenotypic variability remain to be elucidated. We initially investigatedthree patients with heteroplasmic disease associated mutations of mtDNA forthe presence of cis mutations in the major non- coding region that mightinfluence their origins or pathology. A T --> C transition at nt 16 189previously identified in one patient with the 3243 G:C mutation wasassociated with heteroplasmic length variation. Identical length variationwas found in patient-derived cybrid lines containing 0-97.5% 3243 G:C.Similarly, heteroplasmic length variation was demonstrated in 2/6 otherprobands with both the 3243 mutation and the 16,189 polymorphism. Thedistribution of length variants in probands and in asymptomatic familymembers was identical in all cases. Thus length variation appears to beindependent of the level of 3243 mutant mtDNA and hence probably arosewithin both 3243 G:C and 3243 A:T mtDNAs. We suggest that the 16,189polymorphism reflects a predisposition to the formation or fixation ofseveral different mutations in mitochondrial tRNA-LeuUUR.