ArticleAmerican journal of human genetics2019
TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.
Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 3 of them syntheses that pooled it.
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Who cites it
31 citing papers in PubMed, 3 syntheses or guidelines pooled it, 47 citations in OpenAlex.
- Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder.Nature genetics · 2025Pooled it
- Pooled it
- Neuropathology of genetically defined malformations of cortical development-A systematic literature review.Neuropathology and applied neurobiology · 2021Pooled it
- Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.Genome biology · 2020Trial
- Role of mitochondria-associated ER membranes in lipid metabolism: implications for renal lipotoxicity.Bioscience reports · 2026Review
- TMX2-Related Neurodevelopmental Disorder With Bilateral Polymicrogyria and Syndactyly: A Case Report From Morocco.Cureus · 2026Article
- Therapeutic potential of TMSC-Exo for non-alcoholic fatty liver disease using the liver-on-a-chip model.Journal of translational internal medicine · 2026Article
- Long-read DNA and RNA sequencing reveal an intronic retrotransposon insertion in TCOF1 causing Treacher Collins syndrome.HGG advances · 2026Article
- Endoplasmic Reticulum Redoxome: Protein Folding and Beyond.Biochemistry · 2026Review
- Glucose restriction induces degeneration of neurons with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer.Molecular psychiatry · 2025Article
- The non-canonical thioreductase Tmx2b is essential for neuronal survival during zebrafish embryonic brain development.Development (Cambridge, England) · 2025Article
- Disturbances of endoplasmic reticulum proteostasis in neurodevelopmental disorders.Biochemical Society transactions · 2025Review
- Tmx2 Maintains Mitochondrial Function to Support Preimplantation Embryogenesis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for osteoporosis.Osteoporosis and sarcopenia · 2025Article
- Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder.medRxiv : the preprint server for health sciences · 2025Article
- TMX2 potentiates cell viability of hepatocellular carcinoma by promoting autophagy and mitophagy.Autophagy · 2024Article
- Research Advances in Neuroblast Migration in Traumatic Brain Injury.Molecular neurobiology · 2024Review
- Influence of TMX2-CTNND1 polymorphism on cortical thickness in schizophrenia patients and unaffected siblings: an exploratory study based on target region sequencing.Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) · 2024Article
- Article
- SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes.Brain : a journal of neurology · 2023Article
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Authors and funding
49 authors at 20 institutions in 14 countries.
Funding
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.
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