Published online 11 February 2004
Nucleic Acids Research, 2004, Vol. 32, No. 3 867-877
© 2004 Oxford University Press
Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness
1 Division and Program in Human Genetics and Center for Hearing and Deafness Research, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA, 2 Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA, 3 Boston University School of Medicine, Boston, MA 02118, USA, 4 House Ear Clinic and House Ear Institute, Los Angeles, CA 90057, USA and 5 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
*To whom correspondence should be addressed. Tel: +1 513 636 3337; Fax: +1 513 636 3486; Email: min-xin.guan{at}chmcc.org
We report here the biochemical characterization of the deafness-associated mitochondrial tRNASer(UCN) T7511C mutation, in conjunction with homoplasmic ND1 T3308C and tRNAAla T5655C mutations using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from an African family into human mtDNA-less (
°) cells. Three cybrids derived from an affected matrilineal relative carrying the homoplasmic T7511C mutation, exhibited 
75% decrease in the tRNASer(UCN) level, compared with three control cybrids. This amount of reduction in the tRNASer(UCN) level is below a proposed threshold to support a normal rate of mitochondrial protein synthesis in lymphoblastoid cell lines. This defect is likely a primary contributor to 52% reduction in the rate of mitochondrial protein synthesis and marked defects in respiration and growth properties in galactose-containing medium. Interestingly, the T5655C mutation produces 50% reduction in the tRNAAla level in mutant cells. Strikingly, the T3308C mutation causes a significant decrease both in the amount of ND1 mRNA and co-transcribed tRNALeu(UUR) in mutant cells. Thus, mitochondrial dysfunctions caused by the T5655C and T3308C mutations may modulate the phenotypic manifestation of the T7511C mutation. These observations imply that a combination of the T7511C mutation with two mtDNA mutations accounts for the high penetrance of deafness in this family.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. F. Mehler and J. S. Mattick Noncoding RNAs and RNA Editing in Brain Development, Functional Diversification, and Neurological Disease Physiol Rev, July 1, 2007; 87(3): 799 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Qu, R. Li, X. Zhou, Y. Tong, F. Lu, Y. Qian, Y. Hu, J. Q. Mo, C. E. West, and M.-X. Guan The Novel A4435G Mutation in the Mitochondrial tRNAMet May Modulate the Phenotypic Expression of the LHON-Associated ND4 G11778A Mutation Invest. Ophthalmol. Vis. Sci., February 1, 2006; 47(2): 475 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhao, W.-Y. Young, Q. Yan, R. Li, J. Cao, Q. Wang, X. Li, J. L. Peters, D. Han, and M.-X. Guan Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss Nucleic Acids Res., February 18, 2005; 33(3): 1132 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Li, J H Greinwald Jr, L Yang, D I Choo, R J Wenstrup, and M-X Guan Molecular analysis of the mitochondrial 12S rRNA and tRNASer(UCN) genes in paediatric subjects with non-syndromic hearing loss J. Med. Genet., August 1, 2004; 41(8): 615 - 620. [Full Text] [PDF]
|
|