A novel mutation in the mitochondrial tRNA LeuCUN gene associated with a mitochondrial myopathy with respiratory impairment

Mutations in mitochondrially encoded tRNA genes have been described in a variety of neurological disorders. Predominant phenotypes have been observed with the relatively common A3243G tRNALeu(UUR) and A8344G mutations, MELAS, progressive external ophthalmoplegia and diabetes for the former, and MERRF for the latter. However both the range of clinical variability and the extent of genetic defects are extremely large but only few cases of mutations in tRNA LeuCUN gene are described. We identified a novel G12316A transition in the mitochondrial DNA tRNA LeuCUN gene in a 70 years old patient with juvenile myopathy, late onset ptosis, ophthalmoparesis and respiratory impairment. She presented at the age of 16 years a progressive lower limb girdle muscle weakness with waddling gait and generalized fatigability, followed by slowly progressive upper limb, facial, respiratory and extraocular muscle involvement. Family history was negative. A muscle biopsy showed a large number of cytochrome c oxidase negative fibers, including some with the ragged-red features. Southern blot analysis of muscle derived DNA resulted normal. PCR showed several deleted molecules. The complete sequence analysis of the mitochondrial genome showed a novel heteroplasmic G12316A mutation within the tRNA LeuCUN gene, affecting the T-stem domain of this tRNA. The degree of heteroplasmy was lower in blood derived DNA; single fiber analysis showed an higher level of heteroplasmy in ragged-red and COX deficient fibers compared to histochemical normal muscle fibers. The G12316A mutation affects a strictly conserved base pair of the gene and was not found in controls, thus satisfying the accepted criteria for pathogenicity. Mutations in tRNA LeuCUN gene are extremely rare. So we consider that our data increase the genetic and clinical heterogeneity of mitochondrial diseases caused by mutations in mitochondrially encoded tRNA genes.