Human Molecular Genetics Advance Access [Accepted Manuscript] published online on October 16, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp477
Analysis of mouse models of cytochrome c oxidase deficiency due to mutations in Sco2
1 Department of Neurology, Columbia University Medical Center, New York, NY 2 Department of Genetics and Development, Columbia University Medical Center, New York, NY 3 Department of Neurology and Neuroscience,Weill Medical College of Cornell University, New York, NY 4 Department of Environmental Health Sciences, Columbia University Medical Center, New York, NY 5 Department of Medicine, Columbia University Medical Center, New York, NY
* To whom correspondence should be addressed: Dr. Eric A. Schon, Columbia University Medical Center, 1150 St. Nicholas Ave., Berrie-303A, New York, NY 10032. Tel: 212-851-5532; Fax: 212-305-3986; E-mail eas3{at}columbia.edu.
Received August 7, 2009; Revised October 12, 2009; Accepted October 12, 2009
Mutations in SCO2, a protein required for the proper assembly and functioning of cytochrome c oxidase (COX; complex IV of the mitochondrial respiratory chain), cause a fatal infantile cardioencephalomyopathy with COX deficiency. We have generated mice harboring a Sco2 knock-out (KO) allele and a Sco2 knock-in (KI) allele expressing an E
K mutation at position 129 (E129K), corresponding to the E140K mutation found in almost all human SCO2-mutated patients. Whereas homozygous KO mice were embryonic lethals, homozygous KI and compound heterozygous KI/KO mice were viable, but had muscle weakness; biochemically, they had respiratory chain deficiencies as well as complex IV assembly defects in multiple tissues. There was a concomitant reduction in mitochondrial copper content, but the total amount of copper in examined tissues was not reduced. These mouse models should be of use in further studies of Sco2 function, as well as in testing therapeutic approaches to treat the human disorder.
These authors contributed equally to this work.
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