Mutations in mitochondrially encoded
tRNA genes have been described in a variety of
neurological disorders. One such mutation, the A to G transition at
nucleotide position 4336 of the mitochondrial
tRNA(Gln) gene, has been associated with both Alzheimer and
Parkinson disease. We have now performed a complete sequence analysis of all 22 mitochondrially encoded
tRNA genes in 20 cases of histologically proven
idiopathic Parkinson disease. Genomic
DNA extracted from the substantia nigra of frozen or
formalin-fixed and
paraffin-embedded brains was used for amplification by polymerase chain reaction followed by automated sequencing. Two new homoplasmic point mutations were detected in the genes for
tRNA(Thr) (15950 G/A) and
tRNA(Pro) (15965 T/C) in 1 patient each. Restriction
enzyme digestion revealed absence of the 15950 G/A mutation in 96 controls and in 40 cases of neuropathologically confirmed
Alzheimer disease. The 15965 T/C mutation was shown to be absent from 100 control subjects and 47 Alzheimer cases. In addition to the two novel mutations, six known sequence variants were detected in a total of 6 different patients in the genes for
tRNA(Asp) (G7521A, 1),
tRNA(Arg) (T10463C, 1),
tRNA(LeuCUN) (A12308G, 2), and
tRNA(Thr) (A15924G, 1; G15928A, 2), including 1 patient carrying the
tRNA(Gln) (A4336G) mutation. The G15950A transition affects position 70 of the aminoacyl acceptor stem of
tRNA(Thr), which has been implicated as a recognition
element for
threonyl-tRNA synthetase and, at least in some tRNAs, in the processing of primary mitochondrial transcripts. The T15965C point mutation in the mitochondrial
tRNA(Pro) gene alters position 64 of the TpsiC stem. The corresponding
nucleotide in bacterial aminoacyl-tRNAs is involved in the interaction with
elongation factor Tu. Thus, the two novel mutations are likely to be of functional relevance and could contribute to dopaminergic nerve cell death in affected individuals.