• Rachel Schot
  • Chiara Milanese
  • Daphne J Smits
  • Esmee Kasteleijn
  • Andrew E Fry
  • Daniela T Pilz
  • Esra Börklü-Yücel
  • Marco Post
  • Nadia Bahi-Buisson
  • María José Sánchez-Soler
  • Marjon van Slegtenhorst
  • Boris Keren
  • Alexandra Afenjar
  • Stephanie A Coury
  • Wen-Hann Tan
  • Renske Oegema
  • Linda S de Vries
  • Katherine A Fawcett
  • Peter G J Nikkels
  • Aida Bertoli-Avella
  • Amal Al Hashem
  • Abdulmalik A Alwabel
  • Kalthoum Tlili-Graiess
  • Stephanie Efthymiou
  • Faisal Zafar
  • Nuzhat Rana
  • Farah Bibi
  • Henry Houlden
  • Reza Maroofian
  • Richard E Person
  • Amy Crunk
  • Juliann M Savatt
  • Lisbeth Turner
  • Mohammad Doosti
  • Ehsan Ghayoor Karimiani
  • Nebal Waill Saadi
  • Javad Akhondian
  • Maarten H Lequin
  • Hülya Kayserili
  • Peter J van der Spek
  • Johan M Kros
  • Robert M Verdijk
  • Nataša Jovanov Milošević
  • Maarten Fornerod
  • Pier Giorgio Mastroberardino
  • Grazia M S Mancini

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.

Original languageEnglish
Pages (from-to)1126-1147
Number of pages22
JournalAmerican Journal of Human Genetics
Issue number6
Early online date12 Nov 2019
Publication statusPublished - 5 Dec 2019

    Research areas

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

ID: 48397731