PXD037867

PXD037867 is an original dataset announced via ProteomeXchange.

Title	MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention
Description	MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiologic defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:33:07.089.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dimitris Papageorgiou
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-31 09:28:07	ID requested
1	2023-02-20 09:22:05	announced
⏵ 2	2023-11-14 08:33:10	announced	2023-11-14: Updated project metadata.

Weigel B, Tegethoff JF, Grieder SD, Lim B, Nagarajan B, Liu YC, Truberg J, Papageorgiou D, Adrian-Segarra JM, Schmidt LK, Kaspar J, Poisel E, Heinzelmann E, Saraswat M, Christ M, Arnold C, Ibarra IL, Campos J, Krijgsveld J, Monyer H, Zaugg JB, Acuna C, Mall M, MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention. Mol Psychiatry, 28(5):2122-2135(2023) [pubmed]

submitter keyword: MYT1L, autism, human neurons

Jeroen Krijgsveld
contact affiliation	Division head B230 Proteomics of Stem Cells and Cancer
contact email	j.krijgsveld@dkfz-heidelberg.de
lab head
Dimitris Papageorgiou
contact affiliation	Post-Doctoral Scientist
contact email	d.papageorgiou@dkfz.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD037867
     1. Label: PRIDE project
     2. Name: MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention