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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.

In: American Journal of Human Genetics, Vol. 105, No. 6, 05.12.2019, p. 1126-1147.

Research output: Contribution to journalArticle

Harvard

Vandervore, LV, Schot, R, Milanese, C, Smits, DJ, Kasteleijn, E, Fry, AE, Pilz, DT, Brock, S, Börklü-Yücel, E, Post, M, Bahi-Buisson, N, Sánchez-Soler, MJ, van Slegtenhorst, M, Keren, B, Afenjar, A, Coury, SA, Tan, W-H, Oegema, R, de Vries, LS, Fawcett, KA, Nikkels, PGJ, Bertoli-Avella, A, Al Hashem, A, Alwabel, AA, Tlili-Graiess, K, Efthymiou, S, Zafar, F, Rana, N, Bibi, F, Houlden, H, Maroofian, R, Person, RE, Crunk, A, Savatt, JM, Turner, L, Doosti, M, Karimiani, EG, Saadi, NW, Akhondian, J, Lequin, MH, Kayserili, H, van der Spek, PJ, Jansen, AC, Kros, JM, Verdijk, RM, Milošević, NJ, Fornerod, M, Mastroberardino, PG & Mancini, GMS 2019, 'TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities', American Journal of Human Genetics, vol. 105, no. 6, pp. 1126-1147. https://doi.org/10.1016/j.ajhg.2019.10.009

APA

Vandervore, L. V., Schot, R., Milanese, C., Smits, D. J., Kasteleijn, E., Fry, A. E., ... Mancini, G. M. S. (2019). TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities. American Journal of Human Genetics, 105(6), 1126-1147. https://doi.org/10.1016/j.ajhg.2019.10.009

Vancouver

Vandervore LV, Schot R, Milanese C, Smits DJ, Kasteleijn E, Fry AE et al. TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities. American Journal of Human Genetics. 2019 Dec 5;105(6):1126-1147. https://doi.org/10.1016/j.ajhg.2019.10.009

Author

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. / TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities. In: American Journal of Human Genetics. 2019 ; Vol. 105, No. 6. pp. 1126-1147.

BibTeX

@article{1f06fab713e547589e0b8faeb95094cd,
title = "TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities",
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",
author = "Vandervore, {Laura V} and Rachel Schot and Chiara Milanese and Smits, {Daphne J} and Esmee Kasteleijn and Fry, {Andrew E} and Pilz, {Daniela T} and Stefanie Brock and Esra B{\"o}rkl{\"u}-Y{\"u}cel and Marco Post and Nadia Bahi-Buisson and S{\'a}nchez-Soler, {Mar{\'i}a Jos{\'e}} and {van Slegtenhorst}, Marjon and Boris Keren and Alexandra Afenjar and Coury, {Stephanie A} and Wen-Hann Tan and Renske Oegema and {de Vries}, {Linda S} and Fawcett, {Katherine A} and Nikkels, {Peter G J} and Aida Bertoli-Avella and {Al Hashem}, Amal and Alwabel, {Abdulmalik A} and Kalthoum Tlili-Graiess and Stephanie Efthymiou and Faisal Zafar and Nuzhat Rana and Farah Bibi and Henry Houlden and Reza Maroofian and Person, {Richard E} and Amy Crunk and Savatt, {Juliann M} and Lisbeth Turner and Mohammad Doosti and Karimiani, {Ehsan Ghayoor} and Saadi, {Nebal Waill} and Javad Akhondian and Lequin, {Maarten H} and H{\"u}lya Kayserili and {van der Spek}, {Peter J} and Jansen, {Anna C} and Kros, {Johan M} and Verdijk, {Robert M} and Milošević, {Nataša Jovanov} and Maarten Fornerod and Mastroberardino, {Pier Giorgio} and Mancini, {Grazia M S}",
note = "Copyright {\circledC} 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = "12",
day = "5",
doi = "10.1016/j.ajhg.2019.10.009",
language = "English",
volume = "105",
pages = "1126--1147",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",

}

RIS

TY - JOUR

T1 - TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities

AU - Vandervore, Laura V

AU - Schot, Rachel

AU - Milanese, Chiara

AU - Smits, Daphne J

AU - Kasteleijn, Esmee

AU - Fry, Andrew E

AU - Pilz, Daniela T

AU - Brock, Stefanie

AU - Börklü-Yücel, Esra

AU - Post, Marco

AU - Bahi-Buisson, Nadia

AU - Sánchez-Soler, María José

AU - van Slegtenhorst, Marjon

AU - Keren, Boris

AU - Afenjar, Alexandra

AU - Coury, Stephanie A

AU - Tan, Wen-Hann

AU - Oegema, Renske

AU - de Vries, Linda S

AU - Fawcett, Katherine A

AU - Nikkels, Peter G J

AU - Bertoli-Avella, Aida

AU - Al Hashem, Amal

AU - Alwabel, Abdulmalik A

AU - Tlili-Graiess, Kalthoum

AU - Efthymiou, Stephanie

AU - Zafar, Faisal

AU - Rana, Nuzhat

AU - Bibi, Farah

AU - Houlden, Henry

AU - Maroofian, Reza

AU - Person, Richard E

AU - Crunk, Amy

AU - Savatt, Juliann M

AU - Turner, Lisbeth

AU - Doosti, Mohammad

AU - Karimiani, Ehsan Ghayoor

AU - Saadi, Nebal Waill

AU - Akhondian, Javad

AU - Lequin, Maarten H

AU - Kayserili, Hülya

AU - van der Spek, Peter J

AU - Jansen, Anna C

AU - Kros, Johan M

AU - Verdijk, Robert M

AU - Milošević, Nataša Jovanov

AU - Fornerod, Maarten

AU - Mastroberardino, Pier Giorgio

AU - Mancini, Grazia M S

N1 - Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2019/12/5

Y1 - 2019/12/5

N2 - 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.

AB - 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.

KW - PDI

KW - SERCA2

KW - TMX2

KW - calnexin

KW - epilepsy

KW - hydrogen peroxide

KW - microcephaly

KW - mitochondria-associated membrane

KW - polymicrogyria

KW - redox

UR - http://www.scopus.com/inward/record.url?scp=85075550737&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2019.10.009

DO - 10.1016/j.ajhg.2019.10.009

M3 - Article

C2 - 31735293

VL - 105

SP - 1126

EP - 1147

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -

ID: 48397731