The mitochondrial DNA transfer RNALeu(UUR) XXXX mutation. A clinical and genetic study.

@entity1 @entity20066 @entity6 @entity75 @entity3914 @entity3055 @entity73269 @entity2319 @entity36611 @entity27379 @entity23355 @entity121
The mitochondrial tRNALeu(UUR) @entity23355 mutation was identified in 22 unrelated @entity1 . The probands and their relatives were assessed clinically and by quantitative mitochondrial DNA (mtDNA) analysis. While 10 probands had clinical features consistent with the syndrome of mitochondrial @entity20066 ( @entity20066 ), usually associated with this mutation, 12 probands had other phenotypes including other @entity75 , @entity3914 ( @entity3914 ), @entity27379 ( @entity27379 ), @entity121 alone and @entity6 and @entity2319 . Histochemical analyses of muscle biopsies showed a higher proportion of cytochrome oxidase (COX) negative fibres, but fewer strongly COX reactive fibres, in @entity1 with @entity3914 compared with those with @entity20066 . The proportion of mutant mtDNA present in blood was significantly greater in symptomatic than asymptomatic subjects, and was correlated with age in both. This correlation was not observed in @entity1 with the tRNALys @entity36611 mutation. The proportion of mutant mtDNA @entity23355 in muscle was always greater than that in blood. Significant correlations between proportion of mutant mtDNA in blood and both age of onset of disease and a clinical severity score were observed. However, the proportion of mutant mtDNA in blood in affected and unaffected cases overlapped, preventing use of the genetic-clinical correlation for prognostic or predictive purposes. The presence of intrafamilial clustering of phenotypes and the imperfect relationship between proportion of mutant mtDNA and the presence or absence of disease suggests that other factors may determine the phenotype. To investigate this possibility further, the tRNALeu(UUR) gene was sequenced in 23 probands and six relatives. In 28 @entity1 the sequence was normal apart from the 3243 mutation, but in members of one family there was a homoplasmic @entity73269 which was not found in 140 controls or 50 other @entity1 with @entity3055 . The family with this transition had high levels of mutant mtDNA @entity23355 , with a unique phenotype of predominant @entity121 , suggesting that this second base change in tRNALeu(UUR) may influence the clinical phenotype.
