Journal Article

<i>FOXRED1</i>, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy

Elisa Fassone, Andrew J. Duncan, Jan-Willem Taanman, Alistair T. Pagnamenta, Michael I. Sadowski, Tatjana Holand, Waseem Qasim, Paul Rutland, Sarah E. Calvo, Vamsi K. Mootha, Maria Bitner-Glindzicz and Shamima Rahman

in Human Molecular Genetics

Volume 19, issue 24, pages 4837-4847
Published in print December 2010 | ISSN: 0964-6906
Published online September 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq414
FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy

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Complex I is the first and largest enzyme in the respiratory chain and is located in the inner mitochondrial membrane. Complex I deficiency is the most commonly reported mitochondrial disorder presenting in childhood, but the molecular basis of most cases remains elusive. We describe a patient with complex I deficiency caused by mutation of the molecular chaperone FOXRED1. A combined homozygosity mapping and bioinformatics approach in a consanguineous Iranian-Jewish pedigree led to the identification of a homozygous mutation in FOXRED1 in a child who presented with infantile-onset encephalomyopathy. Silencing of FOXRED1 in human fibroblasts resulted in reduced complex I steady-state levels and activity, while lentiviral-mediated FOXRED1 transgene expression rescued complex I deficiency in the patient fibroblasts. This FAD-dependent oxidoreductase, which has never previously been associated with human disease, is now shown to be a complex I-specific molecular chaperone. The discovery of the c.1054C>T; p.R352W mutation in the FOXRED1 gene is a further contribution towards resolving the complex puzzle of the genetic basis of human mitochondrial disease.

Journal Article.  6156 words.  Illustrated.

Subjects: Genetics and Genomics

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