TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities
Vandervore, Laura V; Schot, Rachel; Milanese, Chiara; Smits, Daphne J; Kasteleijn, Esmee; Fry, Andrew E; Pilz, Daniela T; Brock, Stefanie; Börklü-Yücel, Esra; Post, Marco; Bahi-Buisson, Nadia; Sánchez-Soler, María José; van Slegtenhorst, Marjon; Keren, Boris; Afenjar, Alexandra; Coury, Stephanie A; Tan, Wen-Hann; Oegema, Renske; de Vries, Linda S; Fawcett, Katherine A; Nikkels, Peter G J; Bertoli-Avella, Aida; Al Hashem, Amal; Alwabel, Abdulmalik A; Tlili-Graiess, Kalthoum; Efthymiou, Stephanie; Zafar, Faisal; Rana, Nuzhat; Bibi, Farah; Houlden, Henry; Maroofian, Reza; Person, Richard E; Crunk, Amy; Savatt, Juliann M; Turner, Lisbeth; Doosti, Mohammad; Karimiani, Ehsan Ghayoor; Saadi, Nebal Waill; Akhondian, Javad; Lequin, Maarten H; Kayserili, Hülya; van der Spek, Peter J; Jansen, Anna C; Kros, Johan M; Verdijk, Robert M; Milošević, Nataša Jovanov; Fornerod, Maarten; Mastroberardino, Pier Giorgio; Mancini, Grazia M S
(2019) American Journal of Human Genetics, volume 105, issue 6, pp. 1126 - 1147
(Article)
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
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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.
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Keywords: PDI, SERCA2, TMX2, calnexin, epilepsy, hydrogen peroxide, microcephaly, mitochondria-associated membrane, polymicrogyria, redox, Genetics, Genetics(clinical)
ISSN: 0002-9297
Publisher: Cell Press
Note: Funding Information: L.V.V. was supported by Steunfonds Marguerite-Marie Delacroix , Research Foundation Flanders ( FWO travel grant V429317N ) and COST Action CA16118 (STSM grant #39032 ). S.B. is supported by the COST Action CA16118 (STSM grant #576 ). E.B.Y. is supported by the COST Action CA16118 (STSM grant #39362 ). A.F., D.T.P., N.B.B., R.O., M.H.L., H.K., A.C.J., N.J.M., and G.M.S.M. are members of the European Network on Brain Malformations, Neuro-MIG (COST Action CA16118). A.E.F. and D.T.P. were supported by the Newlife Foundation for Disabled Children (Grant reference: 11-12/04 ), Wales Epilepsy Research Network , and Wales Gene Park . A.C.J. is supported by a Senior Clinical Investigator Fellowship from the FWO . G.M.S.M. is supported by the ZonMW TOP grant #91217045 and by private donations. Data from families 8, 9, and 10 were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award ( Synaptopathies ) funding ( WT093205 MA and WT104033AIA ). This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre . The studies were funded by the Medical Research Council (MRC) ( MR/S01165X/1 , MR/S005021/1 , and G0601943 ), the National Institute for Health Research University College London Hospitals Biomedical Research Centre , the Rosetree Trust , Ataxia UK , the Multiple System Atrophy (MSA) Trust , Brain Research UK , Sparks Great Ormand Street Hospital (GOSH) Charity , Muscular Dystrophy UK (MDUK), and the Muscular Dystrophy Association (MDA USA). Funding Information: We thank the families for participating in this study. This publication is, in part, a result of collaboration within the European Network on Brain Malformations funded by COST (European Cooperation in Science and Technology, Action CA16118). We thank Dr. Mark Nellist for sharing materials for IP experiments, Drs. Jeroen A.A. Demmers and Dick H.W. Dekkers of the Proteomics Center core facility, Erasmus University Medical Center, for help with mass spectrometry, Dr. Frans W. Verheijen for critically reading the manuscript, and Professor Dr Robert Hofstra for continuous support. We thank the Erasmus MC Cancer Computational Biology Center for giving access to their IT infrastructure and the software that was used for various computations and data analyses in this study. L.V.V. was supported by Steunfonds Marguerite-Marie Delacroix, Research Foundation Flanders (FWO travel grant V429317N) and COST Action CA16118 (STSM grant #39032). S.B. is supported by the COST Action CA16118 (STSM grant #576). E.B.Y. is supported by the COST Action CA16118 (STSM grant #39362). A.F. D.T.P. N.B.B. R.O. M.H.L. H.K. A.C.J. N.J.M. and G.M.S.M. are members of the European Network on Brain Malformations, Neuro-MIG (COST Action CA16118). A.E.F. and D.T.P. were supported by the Newlife Foundation for Disabled Children (Grant reference: 11-12/04), Wales Epilepsy Research Network, and Wales Gene Park. A.C.J. is supported by a Senior Clinical Investigator Fellowship from the FWO. G.M.S.M. is supported by the ZonMW TOP grant #91217045 and by private donations. Data from families 8, 9, and 10 were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The studies were funded by the Medical Research Council (MRC) (MR/S01165X/1, MR/S005021/1, and G0601943), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the Rosetree Trust, Ataxia UK, the Multiple System Atrophy (MSA) Trust, Brain Research UK, Sparks Great Ormand Street Hospital (GOSH) Charity, Muscular Dystrophy UK (MDUK), and the Muscular Dystrophy Association (MDA USA). Publisher Copyright: © 2019 American Society of Human Genetics
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