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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.

SUBMITTER: Vandervore LV 

PROVIDER: S-EPMC6904804 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Vandervore Laura V LV   Schot Rachel R   Milanese Chiara C   Smits Daphne J DJ   Kasteleijn Esmee E   Fry Andrew E AE   Pilz Daniela T DT   Brock Stefanie S   Börklü-Yücel Esra E   Post Marco M   Bahi-Buisson Nadia N   Sánchez-Soler María José MJ   van Slegtenhorst Marjon M   Keren Boris B   Afenjar Alexandra A   Coury Stephanie A SA   Tan Wen-Hann WH   Oegema Renske R   de Vries Linda S LS   Fawcett Katherine A KA   Nikkels Peter G J PGJ   Bertoli-Avella Aida A   Al Hashem Amal A   Alwabel Abdulmalik A AA   Tlili-Graiess Kalthoum K   Efthymiou Stephanie S   Zafar Faisal F   Rana Nuzhat N   Bibi Farah F   Houlden Henry H   Maroofian Reza R   Person Richard E RE   Crunk Amy A   Savatt Juliann M JM   Turner Lisbeth L   Doosti Mohammad M   Karimiani Ehsan Ghayoor EG   Saadi Nebal Waill NW   Akhondian Javad J   Lequin Maarten H MH   Kayserili Hülya H   van der Spek Peter J PJ   Jansen Anna C AC   Kros Johan M JM   Verdijk Robert M RM   Milošević Nataša Jovanov NJ   Fornerod Maarten M   Mastroberardino Pier Giorgio PG   Mancini Grazia M S GMS  

American journal of human genetics 20191114 6


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 familie  ...[more]

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