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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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Project description:Objectives: Development of daptomycin resistance (DAPR) in Staphylococcus aureus is associated with clinical treatment failures. Mechanism(s) of such resistance has not been clearly defined. Methods: We studied an isogenic daptomycin-susceptible (DAPS) and daptomycin-resistant (DAPR) S. aureus strain pair (616; 701) from a patient with relapsing endocarditis during daptomycin treatment, using comparative transcriptomic and proteomic techniques. Results. Minor differences in genome content were found between strains by DNA hybridization. Transcriptomic analyses identified a number of genes differentially expressed in important functional categories: cell division, metabolism of bacterial envelopes and global regulation. Of note, the DAPR isolate exhibited reduced expression of the major cell wall autolysis gene coincident with upregulation of genes involved in wall teichoic acid production. Using quantitative (q)RT-PCR on gene cadre putatively involved in cationic peptide resistance, we formulated a putative regulatory network compatible with microarray data-sets, mainly implicating bacterial envelopes. Of interest, qRT-PCR of this same gene cadre from two distinct isogenic DAPS/DAPR clinical strain pairs revealed evidence of other strain dependent networks operative in the DAPR phenotype. Comparative proteomics of 616 vs 701 revealed differential abundance of proteins in various functional categories including: cell-wall associated targets and biofilm-formation proteins. Phenotypically, strains 616 and 701 showed major differences in ability to develop bacterial biofilms in presence of the antibacterial lipid, oleic acid. Conclusions: Compatible with previous in vitro observations, in vivo acquired DAPR in S. aureus is a complex, multistep phenomenon allowing for: i) strain dependent phenotypes; ii) transcriptome adaptation; and iii) modification of lipid and protein content of cellular envelopes. Daptomycin suceptible strain vs daptomycin non suceptible strain after daptomycin treatment

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

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