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Am J Hum Genet. 2019 Dec 5;105(6):1126-1147. doi: 10.1016/j.ajhg.2019.10.009. Epub 2019 Nov 14.

TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.

Author information

1
Department of Clinical Genetics, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands; Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels 1090, Belgium; Center for Medical Genetics, UZ Brussel, Brussels 1090, Belgium.
2
Department of Clinical Genetics, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
3
Department of Molecular Genetics, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
4
Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
5
West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
6
Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels 1090, Belgium; Department of Pathology, UZ Brussels, Brussels 1090, Belgium.
7
Department of Clinical Genetics, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands; Department of Cell Biology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands; Medical Genetics Department, Koç University School of Medicine, Istanbul 34010, Turkey.
8
Department of Cell Biology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
9
Imagine Institute, INSERM UMR-1163, Laboratory Genetics and Embryology of Congenital Malformations, Paris Descartes University, Institut des Maladies Génétiques 24, Boulevard de Montparnasse, Paris 75015, France.
10
Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia 30120, España.
11
Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris 75013, France.
12
Département de génétique et embryologie médicale, CRMR des malformations et maladies congénitales du cervelet et des déficits intellectuels de causes rares, GRC n°19, pathologies Congénitales du Cervelet-LeucoDystrophies, Sorbonne Universités, Hôpital Trousseau, Paris 75012, France.
13
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
14
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
15
Department of Genetics, University Medical Center Utrecht, Utrecht University, 3584 CX, the Netherlands.
16
Department of Neonatology, University Medical Center Utrecht, Utrecht University, 3584 CX, the Netherlands.
17
Medical Research Council (MRC) Computational Genomics Analysis and Training Programme, MRC Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
18
Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584 CX, the Netherlands.
19
Centogene AG, Rostock 18055, Germany.
20
Division of Medical Genetic, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 12233, Saudi Arabia.
21
Division of General Pediatrics, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 12233, Saudi Arabia.
22
Division of Neuroradiology, Department of Radiology, Prince Sultan Military Medical City, Riyadh 12233, Saudi Arabia.
23
Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
24
Department of Pediatric Neurology, Children's Hospital and Institute of Child Health, Multan 60000, Pakistan.
25
University Institute of Biochemistry & Biotechnology, PMAS - Arid Agriculture University, Rawalpindi 43600, Pakistan.
26
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
27
The Autism & Developmental Medicine Institute at Geisinger, Danville, PA 17822, USA.
28
Department of Molecular Genetics, Next Generation Genetic Polyclinic, Mashhad 009851, Iran.
29
Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace London, SW17 ORE, UK; Innovative Medical Research Center, Mashhad Branch, Islamic Azdad University, Mashhad 9133736351, Iran.
30
College of Medicine / Baghdad University, Children Welfare Teaching Hospital, Medical City Complex, Baghdad 10001, Iraq.
31
Department of Pediatric Neurology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad 009851, Iran.
32
Department of Radiology, University Medical Center Utrecht, Utrecht, 3584 CX, the Netherlands.
33
Medical Genetics Department, Koç University School of Medicine, Istanbul 34010, Turkey.
34
Department of Pathology, Clinical Bio-informatics, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
35
Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels 1090, Belgium; Pediatric Neurology Unit, Department of Pediatrics, Universitair Ziekenhuis Brussel, Brussels 1090, Belgium.
36
Department of Pathology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
37
Croatian Institute of Brain Research, School of Medicine, University of Zagreb, Zagreb 10000, Croatia.
38
Department of Molecular Genetics, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands; Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila 67100, Italy.
39
Department of Clinical Genetics, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands. Electronic address: g.mancini@erasmusmc.nl.

Abstract

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.

KEYWORDS:

PDI; SERCA2; TMX2; calnexin; epilepsy; hydrogen peroxide; microcephaly; mitochondria-associated membrane; polymicrogyria; redox

PMID:
31735293
PMCID:
PMC6904804
[Available on 2020-06-05]
DOI:
10.1016/j.ajhg.2019.10.009

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