RT Journal Article
T1 Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency
A1 Barbosa Gouveia, Sofia
A1 González Vioque, Emiliano
A1 Borges, Filipa
A1 Gutiérrez Solana, Luís G.
A1 Wintjes, Liesbeth
A1 Kappen, Antonia
A1 Heuvel, Lambert van den
A1 Leis Trabazo, María Rosaura
A1 Rodenburg, Richard
A1 Couce Pico, María Luz
K1 Mitochondrial disorders
K1 Complex I deficiency
K1 FOXRED1
K1 Epilepsy
AB Complex 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 defects
PB MDPI
YR 2019
FD 2019
LK http://hdl.handle.net/10347/23851
UL http://hdl.handle.net/10347/23851
LA eng
NO Barbosa-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, 1262
NO This study was supported with a competitive Ph.D. grant by Pre-Doctoral scholarship, for research groups of the Health Research Institute of Santiago (IDIS)
DS Minerva
RD 3 may 2026