Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene

Autoren

Katharina Maniura-Weber
Mark Helm
Katrin Engemann
Sabrina Eckertz
Myriam Möllers
Matthias Schauen
Armine Hayrapetyan
Jürgen-Christoph von Kleist-Retzow
Robert N Lightowlers
Laurence A Bindoff
Rudolf J Wiesner

DOI

10.1093/nar/gkl727

eISSN

1362-4962

ISSN

0305-1048

Ausgabe der Veröffentlichung

22

Zeitschrift

Nucleic Acids Research

Sprache

en

Online publication date

2006

Paginierung

6404 - 6415

Datum der Veröffentlichung

2006

Status

Published

Herausgeber

Oxford University Press (OUP)

Herausgeber URL

http://dx.doi.org/10.1093/nar/gkl727

Datum der Datenerfassung

2021

Titel

Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene

Ausgabe der Zeitschrift

34

Data source: Crossref

Abstract

The gene encoding mt-tRNA(Leu(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-tRNA(Leu(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-tRNA(Leu(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.

Addresses

Institute of Vegetative Physiology, Medical Faculty, University of Köln, Robert-Koch-Strasse 39, D-50931 Köln, Germany.

Autoren

Katharina Maniura-Weber
Mark Helm
Katrin Engemann
Sabrina Eckertz
Myriam Möllers
Matthias Schauen
Armine Hayrapetyan
Jürgen-Christoph von Kleist-Retzow
Robert N Lightowlers
Laurence A Bindoff
Rudolf J Wiesner

DOI

10.1093/nar/gkl727

eISSN

1362-4962

Externe Identifier

PubMed Identifier: 17130166
PubMed Central ID: PMC1702489

Funding acknowledgements

Wellcome Trust: 074454

Open access

true

ISSN

0305-1048

Ausgabe der Veröffentlichung

22

Zeitschrift

Nucleic acids research

Schlüsselwörter

Muscle, Skeletal
Clone Cells
Mitochondria
Humans
Mitochondrial Myopathies
RNA Precursors
RNA
RNA, Transfer, Leu
Cell Proliferation
RNA Stability
Transfer RNA Aminoacylation
Electron Transport
Genotype
Point Mutation
Genes, Mitochondrial
RNA, Mitochondrial

Sprache

eng

Medium

Print-Electronic

Online publication date

2006

Open access status

Open Access

Paginierung

6404 - 6415

Datum der Veröffentlichung

2006

Status

Published

Publisher licence

CC BY-NC

Datum der Datenerfassung

2006

Titel

Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene.

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

34

Files

https://academic.oup.com/nar/article-pdf/34/22/6404/11218621/gkl727.pdf https://europepmc.org/articles/PMC1702489?pdf=render

Data source: Europe PubMed Central

Abstract

The gene encoding mt-tRNA(Leu(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-tRNA(Leu(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-tRNA(Leu(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.

Autoren

Katharina Maniura-Weber
Mark Helm
Katrin Engemann
Sabrina Eckertz
Myriam Möllers
Matthias Schauen
Armine Hayrapetyan
Jürgen-Christoph von Kleist-Retzow
Robert N Lightowlers
Laurence A Bindoff
Rudolf J Wiesner

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/17130166

DOI

10.1093/nar/gkl727

eISSN

1362-4962

Externe Identifier

PubMed Central ID: PMC1702489

Funding acknowledgements

Wellcome Trust: 074454

Ausgabe der Veröffentlichung

22

Zeitschrift

Nucleic Acids Res

Schlüsselwörter

Cell Proliferation
Clone Cells
Electron Transport
Genes, Mitochondrial
Genotype
Humans
Mitochondria
Mitochondrial Myopathies
Muscle, Skeletal
Point Mutation
RNA
RNA Precursors
RNA Stability
RNA, Mitochondrial
RNA, Transfer, Leu
Transfer RNA Aminoacylation

Sprache

eng

Country

England

Paginierung

6404 - 6415

PII

gkl727

Datum der Veröffentlichung

2006

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2007

Titel

Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

34

Data source: PubMed

Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene

Files

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