Journal article
Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy
Bi-Xia Ke, Salvatore Pepe, David R Grubb, Jasper C Komen, Adrienne Laskowski, Felicity A Rodda, Belinda M Hardman, James J Pitt, Michael T Ryan, Michael Lazarou, Jane Koleff, Michael MH Cheung, Joseph J Smolich, David R Thorburn
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2012
Abstract
Mitochondrial complex I (CI) deficiency is the most common mitochondrial enzyme defect in humans. Treatment of mitochondrial disorders is currently inadequate, emphasizing the need for experimental models. In humans, mutations in the NDUFS6 gene, encoding a CI subunit, cause severe CI deficiency and neonatal death. In this study, we generated a CI-deficient mouse model by knockdown of the Ndufs6 gene using a gene-trap embryonic stem cell line. Ndufs6(gt/gt) mice have essentially complete knockout of the Ndufs6 subunit in heart, resulting in marked CI deficiency. Small amounts of wild-type Ndufs6 mRNA are present in other tissues, apparently due to tissue-specific mRNA splicing, resulting in ..
View full abstractGrants
Funding Acknowledgements
We thank Andrew Heinmiller for assistance with the acquisition of Vevo 2100 echocardiographic images and the staff from Murdoch Childrens Research Institute's animal facility, Victorian Clinical Genetics Services Pathology Newborn Screening Laboratory, Transgenic Animal Service of Queensland, Royal Children's Hospital Department of Anatomical Pathology, University of Melbourne Electron Microscopy Unit, and Florey Neuroscience Institute Integrative Neuroscience Facility for excellent technical support. This work was supported by grants and a Principal Research Fellowship from the Australian National Health and Medical Research Council (to D. R. T.), the Muscular Dystrophy Association, the SMILE Foundation, the Jenour Foundation, the Financial Markets Foundation for Children, and the Victorian Government's Operational Infrastructure Support Program.