title: Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration.
abstract: Thioredoxin 2 (TXN2; also known as Trx2) is a small mitochondrial redox protein essential for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Exome sequencing in a 16-year-old adolescent suffering from an infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy, uncovered a homozygous stop mutation in TXN2. Analysis of patient-derived fibroblasts demonstrated absence of TXN2 protein, increased reactive oxygen species levels, impaired oxidative stress defence and oxidative phosphorylation dysfunction. Reconstitution of TXN2 expression restored all these parameters, indicating the causal role of TXN2 mutation in disease development. Supplementation with antioxidants effectively suppressed cellular reactive oxygen species production, improved cell viability and mitigated clinical symptoms during short-term follow-up. In conclusion, our report on a patient with TXN2 deficiency suggests an important role of reactive oxygen species homeostasis for human neuronal maintenance and energy metabolism.
authors.affiliation: 1 Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Eliska
authors.initials: E
authors.lastname: Holzerova
authors.affiliation: 3 Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Danhauser
authors.affiliation: 1 Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: 1 Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Kremer
authors.affiliation: 3 Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Melcher
authors.affiliation: 4 Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Ingold
authors.affiliation: 4 Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany 5 Division of Animal Production, Specialty of Bioproduction Science, The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate 020-8550, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Caterina
authors.initials: C
authors.lastname: Terrile
authors.affiliation: 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Wolf
authors.affiliation: 6 Medical Faculty, Department of Diagnostic and Interventional Radiology, University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schaper
authors.affiliation: 3 Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.affiliation: 3 Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Baertling
authors.affiliation: 4 Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Friedmann Angeli
authors.affiliation: 4 Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.affiliation: 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: 1 Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany 7 Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: 1 Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany prokisch@helmholtz-muenchen.de felix.distelmaier@med.uni-duesseldorf.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: 3 Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany prokisch@helmholtz-muenchen.de felix.distelmaier@med.uni-duesseldorf.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
mesh_terms: D002648:Child; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics
chemical_list: D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C467002:TXN2 protein, human; D013879:Thioredoxins
keywords: ROS; idebenone; mitochondria; neurodegeneration; thioredoxin