Nucleic Acids Research Advance Access originally published online on November 27, 2006
Nucleic Acids Research 2006 34(22):6404-6415; doi:10.1093/nar/gkl727
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Nucleic Acids Research, 2006, Vol. 34, No. 22 6404-6415
© 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene
1 Institute of Vegetative Physiology, Medical Faculty, University of Köln Robert-Koch-Strasse 39, D-50931 Köln, Germany 2 Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg Im Neuenheimer Feld 364, 69120 Heidelberg, Germany 3 Center for Molecular Medicine Cologne (CMMC), University of Köln Joseph-Stelzmann-Strasse 52, 50931 Köln, Germany 4 Department of Pediatrics, University of Köln Kerpener Strasse 62, 50924 Köln, Germany 5 School of Neurology, Neurobiology and Psychiatry, Medical School, University of Newcastle upon Tyne UK 6 Department of Neurology, Institute of Clinical Medicine, Haukeland University Hospital, University of Bergen 5021 Bergen, Norway
*To whom correspondence should be addressed. Tel: +49 221 478 3610; Fax: +49 221 478 3538; Email: Rudolf.Wiesner{at}uni-koeln.de
Received August 29, 2006. Revised September 19, 2006. Accepted September 19, 2006.
The gene encoding mt-tRNALeu(UUR), MT-TL1, is a hotspot for pathogenic mtDNA mutations. Amongst the first to be described was the 3302A>G transition which resulted in a substantial accumulation in patient muscle of RNA19, an unprocessed RNA intermediate including mt-16S rRNA, mt-tRNALeu(UUR) and MTND1. We have now been able to further assess the molecular aetiology associated with 3302A>G in transmitochondrial cybrids. Increased steady-state levels of RNA19 was confirmed, although not to the levels previously reported in muscle. This data was consistent with an increase in RNA19 stability. The mutation resulted in decreased mt-tRNALeu(UUR) levels, but its stability was unchanged, consistent with a defect in RNA19 processing responsible for low tRNA levels. A partial defect in aminoacylation was also identified, potentially caused by an alteration in tRNA structure. These deficiencies lead to a severe defect in respiration in the transmitochondrial cybrids, consistent with the profound mitochondrial disorder originally associated with this mutation.
*Correspondence may also be addressed to Prof. Laurence Bindoff. Tel: +47 559 75096; Fax: +47 559 75165; Email: laurence.bindoff{at}helse-bergen.no
Present address: Katharina Maniura-Weber, Empa (Swiss Federal Laboratories for Materials Testing and Technology), Lerchenfeldstrasse 5, 9014 St. Gallen, Switzerland
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors