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Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype

ABSTRACT: 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.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Marija Kojic

LAB HEAD: Brandon Wainwright

PROVIDER: PXD023653 | Pride | 2021-01-19

REPOSITORIES: Pride

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			Action	DRS
	MK_20191021_6600_IDA_C_1_1.group	Other
	MK_20191021_6600_IDA_C_1_1.wiff	Wiff
	MK_20191021_6600_IDA_C_1_1.wiff.scan	Wiff
	MK_20191021_6600_IDA_C_1_10.wiff	Wiff
	MK_20191021_6600_IDA_C_1_10.wiff.scan	Wiff

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Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype

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