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


ABSTRACT: 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.

SUBMITTER: Fassone E 

PROVIDER: S-EPMC4560042 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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

Fassone Elisa E   Duncan Andrew J AJ   Taanman Jan-Willem JW   Pagnamenta Alistair T AT   Sadowski Michael I MI   Holand Tatjana T   Qasim Waseem W   Rutland Paul P   Calvo Sarah E SE   Mootha Vamsi K VK   Bitner-Glindzicz Maria M   Rahman Shamima S  

Human molecular genetics 20100921 24


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 identific  ...[more]

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