Barbosa Gouveia, SofiaGonzález Vioque, EmilianoBorges, FilipaGutiérrez Solana, Luís G.Wintjes, LiesbethKappen, AntoniaHeuvel, Lambert van denLeis Trabazo, María RosauraRodenburg, RichardCouce Pico, María Luz2020-11-272020-11-272019Barbosa-Gouveia, S.; González-Vioque, E.; Borges, F.; Gutiérrez-Solana, L.; Wintjes, L.; Kappen, A.; van den Heuvel, L.; Leis, R.; Rodenburg, R.; Couce, M.L. Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency. J. Clin. Med. 2019, 8, 1262http://hdl.handle.net/10347/23851Complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase) is the largest complex of the mitochondrial oxidative phosphorylation system (OXPHOS) system. Forty-four subunits encoded in nuclear and mitochondrial genomes compose this multiprotein complex, its assembly being a highly complex process involving at least 15 additional nuclear encoded assembly factors. Complex I deficiency is a mitochondrial disorder usually associated with early-onset severe multisystem disorders characterized by highly variable clinical manifestations. Flavin adenine dinucleotide (FAD)-dependent oxidoreductase domain-containing protein 1 (FOXRED1) is a complex I assembly factor. To date, only five patients with mitochondrial complex I deficiency due to mutations in FOXRED1 have been characterized. Here, we describe a child with ataxia, epilepsy and psychomotor developmental delay carrying two heterozygous FOXRED1 variants, c.920G>A (p.Gly307Glu) and c.733+1G>A. We demonstrate the molecular mechanism supporting the pathogenicity of the FOXRED1 variants, showing a clear deficiency of complex I activity. The reduction in the steady-state level of complex I holoenzyme in patient fibroblasts, confirmed the pathogenicity of the variants and showed the molecular mechanism behind their pathogenicity. A comparison of the clinical presentation of the index case with the previously described cases allowed deepening our knowledge about the clinical variability associated with FOXRED1 defectseng© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Mitochondrial disordersComplex I deficiencyFOXRED1Epilepsyjournal article10.3390/jcm80812622077-0383open access