PXD023653-1

PXD023653 is an original dataset announced via ProteomeXchange.

Title	Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype
Description	Neurodevelopmental disorders have a variety of aetiologies and most often these are complex genomic traits involving numerous mutations. Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identified biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulated the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis by reducing expression of the genes that guide cell cycle and translation, and up-regulating protein degradation in neurons and oligodendroglia. This leads to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and defines Elp2 as a key regulator of brain development.
HostingRepository	PRIDE
AnnounceDate	2021-01-19
AnnouncementXML	Submission_2021-01-18_23:55:27.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marija Kojic
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-18 00:38:21	ID requested
⏵ 1	2021-01-18 23:55:28	announced

Dataset with its publication pending

submitter keyword: mouse, brain cortex, Elp2, Elongator complex, intellectual disability, autism, tRNA modifications, epitranscriptome

Brandon Wainwright
contact affiliation	Lab Head, UQ Diamantina Institute,The University of Queensland
contact email	b.wainwright@imb.uq.edu.au
lab head
Marija Kojic
contact affiliation	The University of Queensland Diamantina Institute, Translational Research Institute, the University of Queensland, Brisbane, QLD 4102
contact email	m.kojic@uq.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023653
     1. Label: PRIDE project
     2. Name: Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype