AJHG The American Journal of Human Genetics

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation, dendritic and axonal growth. The relevance of ER-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by biallelic loss of function variants in Thioredoxin (TRX)Related Transmembrane-2 ( TMX2 ), detected by exome sequencing in fourteen 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 signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking 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. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Sophia Children's Hospital Department of Clinical Genetics Postal address P.O. box 2060 3000 CB Rotterdam, NL Visiting address Dr. Molewaterplein 40 3015 GD Rotterdam, NL Contact & route www.erasmusmc.nl Head of Department Prof. dr. R.M.W. Hofstra, PhD Heads of section Mr R.J.H. Galjaard, MD, PhD www.erasmusmc.nl To The Editor of the American Journal of Human Genetics Dr Sara Cullinan Direct dial +31-10-7036915 Fax number +31-10-7043072 Internal postal address Ee2018 E-mail ervo@erasmusmc.nl Our reference AJHG-D-19-00366-R4 Date October 3, 2019 Concerning AJHG-D-19-00366R3 , manuscript title: TMX2 is a key regulator of cellular redox state and its dysfunction causes severe brain developmental abnormalities.