Journal
HUMAN MOLECULAR GENETICS
Volume 19, Issue 24, Pages 4837-4847Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddq414
Keywords
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Funding
- UK Medical Research Council [G0200335]
- Child Health Research Appeal Trust
- Jeans 4 Genes
- Climb and Leukaemia
- Lymphoma research
- Great Ormond Street Hospital Childrens Charity [V1220] Funding Source: researchfish
- Medical Research Council [G0200335] Funding Source: researchfish
- MRC [G0200335] Funding Source: UKRI
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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.
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