#
Publication:

Abnormal RNA processing associated with a novel tRNA mutation in mitochondrial DNA. A potential disease mechanism (1993)

Author(s): L. A. Bindoff;N. Howell;J. Poulton;D. A. McCullough;K. J. Morten;R. N. Lightowlers;D. M. Turnbull;K. Weber

  • : Abnormal RNA processing associated with a novel tRNA mutation in mitochondrial DNA. A potential disease mechanism

Abstract: A patient with a mitochondrial myopathy and biochemically proven profound complex I deficiency has a new mutation in mtDNA. This A-to-G transition at position 3302, involving the aminoacyl stem of tRNA(Leu(UUR)), is associated with abnormal mitochondrial RNA processing. Northern analysis demonstrates marked accumulation of a polycistronic RNA precursor containing sequence for 16 S rRNA, tRNA(Leu(UUR)), and ND1. Comparison of skeletal muscle and skin fibroblasts suggests that the processing error may be quantitatively less severe in this tissue, and biochemical analysis shows that fibroblasts do not express a biochemical defect despite containing the mutation. Important qualitative differences in the processing of this RNA precursor were found when comparing muscle and skin fibroblasts. In muscle, processing appears to occur first at the 5'-end of the tRNA, generating 16 S rRNA plus a tRNA + ND1 intermediate. In fibroblasts, processing occurs at the 3'-end of the tRNA, generating a 16 S rRNA + tRNA intermediate. We suggest that the mutation at position 3302 induces abnormal mitochondrial RNA processing that is linked to the biochemical defect (profound loss of complex I activity), either by qualitative or quantitative abnormalities in the ND1 message. The restriction to skeletal muscle of both the processing error and the biochemical defect suggests that the observed tissue differences in RNA processing play a protective role in skin fibroblasts.

Notes: 0021-9258 Case Reports Journal Article

  • Short Title: Abnormal RNA processing associated with a novel tRNA mutation in mitochondrial DNA. A potential disease mechanism
  • Date: Sep 15
  • Journal: J Biol Chem
  • Volume: 268
  • Issue: 26
  • Pages: 19559-64
  • Publication type: Article
  • Bibliographic status: Published

Keywords: Adult Amino Acid Sequence Animals Anticodon/genetics Base Sequence Blotting, Northern Cells, Cultured Comparative Study DNA, Mitochondrial/*genetics Female Fibroblasts/enzymology Humans Male Mitochondrial Myopathies/enzymology/*genetics Molecular Sequence Data Muscles/*enzymology NAD(P)H Dehydrogenase (Quinone)/*deficiency/*genetics Nucleic Acid Conformation Oligodeoxyribonucleotides Pedigree *Point Mutation Polymerase Chain Reaction/methods RNA Precursors/genetics/*metabolism RNA, Transfer, Leu/biosynthesis/*genetics Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Restriction Mapping Sequence Homology, Nucleic Acid Skin/*enzymology

Staff

Professor Robert Lightowlers
Director, ICaMB and Professor of Molecular Neuroscience