title: 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.
authors.affiliation: Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fassone
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Duncan
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.forename: Alistair T
authors.initials: AT
authors.lastname: Pagnamenta
authors.forename: Michael I
authors.initials: MI
authors.lastname: Sadowski
authors.forename: Tatjana
authors.initials: T
authors.lastname: Holand
authors.forename: Waseem
authors.initials: W
authors.lastname: Qasim
authors.forename: Paul
authors.initials: P
authors.lastname: Rutland
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Calvo
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000378:metabolism*; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D007223:Infant; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: C556294:FOXRED1 protein, human; D018832:Molecular Chaperones; D012333:RNA, Messenger; D005182:Flavin-Adenine Dinucleotide; D042967:Electron Transport Complex I