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

Kojic, Marija; Gawda, Tomasz; Gaik, Monika; Begg, Alexander; Salerno-Kochan, Anna; Kurniawan, Nyoman D.; Jones, Alun; Drożdżyk, Katarzyna; Kościelniak, Anna; Chramiec‐Głąbik, Andrzej; Hediyeh-Zadeh, Soroor; Kasherman, Maria; Shim, Woo Jun; Sinniah, Enakshi; Genovesi, Laura A.; Abrahamsen, Rannvá K.; Fenger, Christina; Madsen, Camilla Gøbel; Cohen, Julie S.; Fatemi, Ali; Stark, Zornitza; Lunke, Sebastian; Lee, Joy; Hansen, Jens Christian; Boxill, Martin Faber; Keren, Boris; Marey, Isabelle; Saenz, Margarita; Brown, Kathleen; Alexander, Suzanne; Mureev, Sergey; Batzilla, Alina; Davis, Melissa J.; Piper, Michael; Bodén, Mikael; Burne, Thomas H. J.; Palpant, Nathan J.; Møller, Rikke S.; Glatt, Sebastian; Wainwright, Brandon J.

doi:10.1038/s41467-021-22888-5

Cited by 35 publications

(47 citation statements)

References 98 publications

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“…The analyses confirmed that no microcephaly was evident, with no significant changes found in the cerebral cortex or hippocampus of the mutant mice (Appendix Fig ). Similar to our previous findings in the Elp2 and Elp6 mutants (Kojic et al , 2018, 2021), widespread Purkinje neuron (PN) degeneration was observed in the cerebella of Elp6L118W animals (Appendix Fig ).…”

Section: Resultssupporting

confidence: 90%

Functional divergence of the two Elongator subcomplexes during neurodevelopment

et al. 2022

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The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental delay, epilepsy, intellectual disability, and motor dysfunction. We determine the structures of human and murine Elp456 subcomplexes and locate the mutated residues. We show that patient-derived mutations in Elp456 affect the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modeling the pathogenic variants in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity, and neurological defects. Foremost, our data indicate previously unrecognized differences of the Elp123 and Elp456 subcomplexes for individual tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.

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Section: Resultssupporting

confidence: 90%

Functional divergence of the two Elongator subcomplexes during neurodevelopment

et al. 2022

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“…ASD remains a ‘disease of theories’, as multiple genes and environmental risk factors are probably involved in its pathogenesis. However, to date, the etiology and pathological mechanism of ASD are still unknown [ 57 ]. The genetic architecture of ASD is complex.…”

Section: Discussionmentioning

confidence: 99%

Genetics of autism spectrum disorder: an umbrella review of systematic reviews and meta-analyses

Qiu

et al. 2022

Transl Psychiatry

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Autism spectrum disorder (ASD) is a class of neurodevelopmental conditions with a large epidemiological and societal impact worldwide. To date, numerous studies have investigated the associations between genetic variants and ASD risk. To provide a robust synthesis of published evidence of candidate gene studies for ASD, we performed an umbrella review (UR) of meta-analyses of genetic studies for ASD (PROSPERO registration number: CRD42021221868). We systematically searched eight English and Chinese databases from inception to March 31, 2022. Reviewing of eligibility, data extraction, and quality assessment were performed by two authors. In total, 28 of 5062 retrieved articles were analyzed, which investigated a combined 41 single nucleotide polymorphisms (SNPs) of nine candidate genes. Overall, 12 significant SNPs of CNTNAP2, MTHFR, OXTR, SLC25A12, and VDR were identified, of which associations with suggestive evidence included the C677T polymorphism of MTHFR (under allelic, dominant, and heterozygote models) and the rs731236 polymorphism of VDR (under allelic and homozygote models). Associations with weak evidence included the rs2710102 polymorphism of CNTNAP2 (under allelic, homozygote, and recessive models), the rs7794745 polymorphism of CNTNAP2 (under dominant and heterozygote models), the C677T polymorphism of MTHFR (under homozygote model), and the rs731236 polymorphism of VDR (under dominant and recessive models). Our UR summarizes research evidence on the genetics of ASD and provides a broad and detailed overview of risk genes for ASD. The rs2710102 and rs7794745 polymorphisms of CNTNAP2, C677T polymorphism of MTHFR, and rs731236 polymorphism of VDR may confer ASD risks. This study will provide clinicians and healthcare decision-makers with evidence-based information about the most salient candidate genes relevant to ASD and recommendations for future treatment, prevention, and research.

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“…The dysfunctional splicing is cell type specific, with neurons being least capable of splicing the mutated pre-mRNA and hence being the cell type most impaired in FD (Slaugenhaupt et al 2001; Cuajungco et al 2003). The Elp1 protein is a key scaffolding subunit of the six-subunit Elongator complex which is essential for tRNA wobble uridine (U34) modifications; in the absence of a functional elongator complex, additions of thiol and methoxycarbonyl-methyl do not occur, which perturbs the translation of mRNAs that preferentially use either AA- or AG-ending codons (Huang et al 2005; Bauer and Hermand 2012; Karlsborn et al 2014; Kojic et al 2021). Consequently, loss of Elp1 function leads to considerable changes in the cellular proteome, which can also indirectly perturb the cellular transcriptome, both of which negatively impact pathways that are critical for neurogenesis and survival (George et al 2013; Chaverra et al 2017; Ohlen et al 2017; Goffena et al 2018; Kojic et al 2021).…”

Section: Introductionmentioning

confidence: 99%

Elp1 is required for development of visceral sensory peripheral and central circuitry

Lefcort

Chaverra

Tolman

et al. 2022

Preprint

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Cardiovascular instability and a blunted respiratory drive in hypoxic conditions, are hallmark features of the genetic sensory and autonomic neuropathy, familial dysautonomia (FD). FD results from a mutation in the gene ELP1, whose encoded protein is a scaffolding subunit of the six subunit Elongator complex. In mice, we and others have shown that Elp1 is essential for the normal development of neural crest derived-dorsal root ganglia (DRG) sensory neurons. Whether Elp1 is also required for development of ectodermal placode-derived visceral sensory receptors which are required for normal baroreception and chemosensory responses, has not been investigated. Using mouse models for FD, our data indicate that in fact the entire circuitry underlying baroreception and chemoreception is impaired due to a requirement for Elp1 not only in the visceral sensory neuron ganglia, but also for normal peripheral target innervation, and in their CNS synaptic partners in the medulla. Thus Elp1 is required in both placode- and neural crest-derived sensory neurons and its reduction aborts the normal development of neuronal circuitry essential for autonomic homeostasis and interoception.

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

Cited by 35 publications

References 98 publications

Functional divergence of the two Elongator subcomplexes during neurodevelopment

Functional divergence of the two Elongator subcomplexes during neurodevelopment

Genetics of autism spectrum disorder: an umbrella review of systematic reviews and meta-analyses

Elp1 is required for development of visceral sensory peripheral and central circuitry

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