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Free Radic Biol Med. 2017 May;106:270-277. doi: 10.1016/j.freeradbiomed.2017.02.040. Epub 2017 Feb 21.

Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy.

Author information

1
Department of Epileptology and Life & Brain Center, University of Bonn, Bonn, Germany. Electronic address: alexei_kudin@yahoo.com.
2
Department of Epileptology and Life & Brain Center, University of Bonn, Bonn, Germany. Electronic address: brain21@gmx.net.
3
Department of Epileptology and Life & Brain Center, University of Bonn, Bonn, Germany. Electronic address: gabor.zsurka@ukb.uni-bonn.de.
4
Department of Epileptology and Life & Brain Center, University of Bonn, Bonn, Germany. Electronic address: kevin.hampel@gmx.de.
5
Department of Epileptology and Life & Brain Center, University of Bonn, Bonn, Germany. Electronic address: christian.elger@ukb.uni-bonn.de.
6
Department of Neurosurgery, University of Bonn, Bonn, Germany. Electronic address: alexander.grote@ukb.uni-bonn.de.
7
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Electronic address: yvonne.weber@uni-tuebingen.de.
8
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Electronic address: holger.lerche@uni-tuebingen.de.
9
Cologne Center for Genomics, University of Cologne, Cologne, Germany. Electronic address: holger.thiele@uni-koeln.de.
10
Cologne Center for Genomics, University of Cologne, Cologne, Germany. Electronic address: nuernberg@uni-koeln.de.
11
Cologne Center for Genomics, University of Cologne, Cologne, Germany. Electronic address: herbert.schulz@uni-koeln.de.
12
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
13
Cologne Center for Genomics, University of Cologne, Cologne, Germany. Electronic address: sandert@uni-koeln.de.
14
Division of Biochemistry, Dept. Medical Biochemistry and Biophysics (MBB), Karolinska Institutet, Stockholm, Sweden. Electronic address: Qing.Cheng@ki.se.
15
Division of Biochemistry, Dept. Medical Biochemistry and Biophysics (MBB), Karolinska Institutet, Stockholm, Sweden. Electronic address: elias.arner@ki.se.
16
Institute of Experimental Endocrinology, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: lutz.schomburg@charite.de.
17
Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany. Electronic address: seeher@gmx.de.
18
Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany. Electronic address: nfradejas@uni-bonn.de.
19
Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany. Electronic address: uschweiz@uni-bonn.de.
20
Department of Epileptology and Life & Brain Center, University of Bonn, Bonn, Germany. Electronic address: wolfram.kunz@ukb.uni-bonn.de.

Abstract

Increased oxidative stress has been widely implicated in the pathogenesis in various forms of human epilepsy. Here, we report a homozygous mutation in TXNRD1 (thioredoxin reductase 1) in a family with genetic generalized epilepsy. TXNRD1 is an essential selenium-containing enzyme involved in detoxification of reactive oxygen species (ROS) and redox signaling. The TXNRD1 mutation p.Pro190Leu affecting a highly conserved amino acid residue was identified by whole-exome sequencing of blood DNA from the index patient. The detected mutation and its segregation within the family - all siblings of the index patient were homozygous and the parents heterozygous - were confirmed by Sanger sequencing. TXNRD1 activity was determined in subcellular fractions from a skeletal muscle biopsy and skin fibroblasts of the index patient and the expression levels of the mutated protein were assessed by 75Se labeling and Western blot analysis. As result of the mutation, the activity of TXNRD1 was reduced in the patient's fibroblasts and skeletal muscle (to 34±3% and 16±8% of controls, respectively). In fibroblasts, we detected reduced 75Se-labeling of the enzyme (41±3% of controls). An in-depth in vitro kinetic analysis of the recombinant mutated TXNRD1 indicated 30-40% lowered kcat/Se values. Therefore, a reduced activity of the enzyme in the patient's tissue samples is explained by (i) lower enzyme turnover and (ii) reduced abundance of the mutated enzyme as confirmed by Western blotting and 75Se labeling. The mutant fibroblasts were also found to be less resistant to a hydrogen peroxide challenge. Our data agree with a potential role of insufficient ROS detoxification for disease manifestation in genetic generalized epilepsy.

KEYWORDS:

Epilepsy; Generalized seizures; Oxidative stress; TXNRD1

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