PXD014064

PXD014064 is an original dataset announced via ProteomeXchange.

Title	TMX2 is a key regulator of cellular redox state and its dysfunction causes severe brain developmental abnormalities.
Description	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 the Thioredoxin (TRX)-Related Transmembrane-2 (TMX2) gene, detected by exome sequencing in ten affected individuals from seven 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 and is the first to be linked to human 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 basal 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 state and identify it as a key adaptive regulator of neuronal proliferation, migration and organization in the developing brain.
HostingRepository	PRIDE
AnnounceDate	2019-11-27
AnnouncementXML	Submission_2019-11-27_03:03:05.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jeroen Demmers
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-29 07:50:04	ID requested
1	2019-11-19 16:09:10	announced
⏵ 2	2019-11-27 03:03:08	announced	2019-11-27: Updated project metadata.

Vandervore LV, Schot R, Milanese C, Smits DJ, Kasteleijn E, Fry AE, Pilz DT, Brock S, B, ö, rkl, ü, -Y, ü, cel E, Post M, Bahi-Buisson N, S, á, nchez-Soler MJ, van Slegtenhorst M, Keren B, Afenjar A, Coury SA, Tan WH, 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, Milo, š, evi, ć NJ, Fornerod M, Mastroberardino PG, Mancini GMS, TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities. Am J Hum Genet, 105(6):1126-1147(2019) [pubmed]

submitter keyword: TMX2, redox state, brain developmental abnormalities

Jeroen Demmers
contact affiliation	Proteomics Center, Erasmus MC, Rotterdam, the Netherlands
contact email	j.demmers@erasmusmc.nl
lab head
Jeroen Demmers
contact affiliation	Proteomics Center, Erasmus University Medical Center, Rotterdam, The Netherlands
contact email	j.demmers@erasmusmc.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014064
     1. Label: PRIDE project
     2. Name: TMX2 is a key regulator of cellular redox state and its dysfunction causes severe brain developmental abnormalities.