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Biochemical characterization of the deafness-associated mitochondrial tRNASer(UCN) A7445G mutation in osteosarcoma cell cybrids.

Abstract
The deafness-associated A7445G mutation in the precursor of mitochondrial tRNA(Ser(UCN)) has been identified in several pedigrees from different ethnic backgrounds. To determine the role of nuclear background in the biochemical manifestation associated with the A7445G mutation, we performed a biochemical characterization of this mutation using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from a New Zealand family into human osteosarcoma mtDNA-less (rho(0)) cells. Compared with three control cybrids, three cybrids derived from an affected matrilineal relative carrying the homoplasmic A7445G mutation exhibited approximately 38-57% decrease in the steady-state level of tRNA(Ser(UCN)), which is less reduced levels than in lymphoblastoid cells in the previous study. Furthermore, approximately 22% reduction in the level of aminoacylation of tRNA(Ser(UCN)) was observed in the mutant cybrid cells. Interestingly, approximately 60-63% decrease of steady-state level of ND6 gene, which belongs to the same precursor as that of tRNA(Ser(UCN)), in cybrid cell lines carrying the A7445G mutation, is more than that observed in lymphoblastoid cells. These observations strongly point out a mechanistic link between the processing defect of the tRNA(Ser(UCN)) precursor and decreased stability of ND6 mRNA precursor. These results also imply the influence of nuclear background on the biochemical phenotype associated with the A7445G mutation.
AuthorsXiaoming Li, Linda S Zhang, Nathan Fischel-Ghodsian, Min-Xin Guan
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 328 Issue 2 Pg. 491-8 (Mar 11 2005) ISSN: 0006-291X [Print] United States
PMID15694374 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • DNA, Mitochondrial
  • RNA, Transfer, Ser
Topics
  • Cell Line
  • DNA, Mitochondrial (genetics)
  • Hearing Loss, Sensorineural (genetics)
  • Humans
  • Lymphocytes (physiology)
  • Osteosarcoma (genetics)
  • Point Mutation
  • RNA, Transfer, Ser (genetics)

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