Publications by authors named "Catherine M Abbott"

The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis.

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  • The translation elongation factor eEF1A2 is crucial for binding aminoacyl-tRNA to the ribosome, and since 2012, 21 harmful variants have been linked to severe neurodevelopmental disorders, including epilepsy and intellectual disabilities.
  • A recent study gathered 26 patients with EEF1A2 variants, revealing a milder clinical profile than previously reported, with higher walking and language skills and lower rates of intellectual disability and epilepsy.
  • The research identified 8 new EEF1A2 variants and suggests that severe and moderate phenotypes are linked to specific protein regions affecting GTP exchange, while milder variants may affect secondary functions, contributing to a broader understanding
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De novo heterozygous missense mutations in EEF1A2, encoding neuromuscular translation-elongation factor eEF1A2, are associated with developmental and epileptic encephalopathies. We used CRISPR/Cas9 to recapitulate the most common mutation, E122K, in mice. Although E122K heterozygotes were not observed to have convulsive seizures, they exhibited frequent electrographic seizures and EEG abnormalities, transient early motor deficits and growth defects.

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All vertebrate species express two independently-encoded forms of translation elongation factor eEF1A. In humans and mice eEF1A1 and eEF1A2 are 92 % identical at the amino acid level, but the well conserved developmental switch between the two variants in specific tissues suggests the existence of important functional differences. Heterozygous mutations in eEF1A2 result in neurodevelopmental disorders in humans; the mechanism of pathogenicity is unclear, but one hypothesis is that there is a dominant negative effect on eEF1A1 during development.

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SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders.

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  • - Identifying the genetic causes of neurodevelopmental disorders, particularly in cis-regulatory elements (CRE), is complex; this study focused on 48 males with X-linked intellectual disability (XLID) and found six rare CRE variants relevant to known XLID genes.
  • - Two variants, FMR1CRE and TENM1CRE, demonstrated different enhancer functions in the zebrafish brain, and mouse models revealed that FMR1CRE affected neurodevelopmental processes, while TENM1CRE did not show any significant phenotypic changes.
  • - Although FMR1CRE appeared to contribute to XLID in one family, determining causative variants in rare CREs is difficult and requires in vivo data, highlighting the challenges of
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In most mouse models of disease, the outward manifestation of a disorder can be measured easily, can be assessed with a trivial test such as hind limb clasping, or can even be observed simply by comparing the gross morphological characteristics of mutant and wild-type littermates. But what if we are trying to model a disorder with a phenotype that appears only sporadically and briefly, like epileptic seizures? The purpose of this Review is to highlight the challenges of modelling epilepsy, in which the most obvious manifestation of the disorder, seizures, occurs only intermittently, possibly very rarely and often at times when the mice are not under direct observation. Over time, researchers have developed a number of ways in which to overcome these challenges, each with their own advantages and disadvantages.

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Heterozygous de novo mutations in EEF1A2, encoding the tissue-specific translation elongation factor eEF1A2, have been shown to cause neurodevelopmental disorders including often severe epilepsy and intellectual disability. The mutational profile is unusual; ~50 different missense mutations have been identified but no obvious loss of function mutations, though large heterozygous deletions are known to be compatible with life. A key question is whether the heterozygous missense mutations operate through haploinsufficiency or a gain of function mechanism, an important prerequisite for design of therapeutic strategies.

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  • Zebrafish serve as effective models for studying human single-gene disorders due to their genetic manipulability and the ability to perform high throughput drug screening, although gene duplication can complicate results by masking phenotypes.
  • Recent research indicates differing outcomes based on the methods used (gene editing vs. morpholino treatment) to create zebrafish mutant lines, particularly in the context of neurodevelopmental disorders linked to the human gene EEF1A2.
  • The study identified four eef1a genes in zebrafish, revealing that while the eef1a2 gene's disruption does not affect lifespan, it could be a useful system for investigating the impacts of mutant human EEF1A2 mRNA.
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The eukaryotic translation elongation factor 1A (eEF1A) has two cell-type specific paralogs, eEF1A1 and eEF1A2. Both paralogs undertake a canonical function in delivering aminoacyl-tRNA to the ribosome for translation, but differences in other functions are emerging. eEF1A1 has been reported to be important for the replication of many viruses, but no study has specifically linked the eEF1A2 paralog.

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The multi-subunit eEF1 complex plays a crucial role in de novo protein synthesis. The central functional component of the complex is eEF1A, which occurs as two independently encoded variants with reciprocal expression patterns: whilst eEF1A1 is widely expressed, eEF1A2 is found only in neurons and muscle. Heterozygous mutations in the gene encoding eEF1A2, EEF1A2, have recently been shown to cause epilepsy, autism, and intellectual disability.

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De novo heterozygous missense mutations in the gene encoding translation elongation factor eEF1A2 have recently been found to give rise to neurodevelopmental disorders. Children with mutations in this gene have developmental delay, epilepsy, intellectual disability and often autism; the most frequently occurring mutation is G70S. It has been known for many years that complete loss of eEF1A2 in mice causes motor neuron degeneration and early death; on the other hand heterozygous null mice are apparently normal.

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  • Recent discoveries of new genetic causes for neurological disorders emphasize the need for experimental models that can help researchers understand the biology behind these conditions.
  • The study focuses on using LUHMES cells, which are human mesencephalic cells able to differentiate into mature neurons, and employs CRISPR/Cas9 technology for gene targeting to introduce specific mutations linked to disorders like Rett syndrome.
  • The findings reveal that gene targeting success varies with the mutation's position in the DNA, and the methods demonstrated here could establish LUHMES cells as valuable models for researching neurogenetic disorders.
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Background: Exome sequencing has led to the discovery of mutations in novel causative genes for epilepsy. One such gene is EEF1A2, encoding a neuromuscular specific translation elongation factor, which has been found to be mutated de novo in five cases of severe epilepsy. We now report on a further seven cases, each with a different mutation, of which five are newly described.

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  • Reverse transcription is vital for HIV-1 replication, and the cellular protein eEF1A interacts directly with the virus's reverse transcriptase (RT), which is essential for the last stages of reverse transcription.
  • Experiments using biolayer interferometry and co-immunoprecipation demonstrated a strong binding affinity between eEF1A and RT, highlighting eEF1A as a key cellular protein that binds to RT.
  • A specific mutation in the RT, W252A, weakened the eEF1A-RT interaction and hindered HIV-1 replication, while the compound didemnin B, which targets eEF1A, effectively inhibited HIV-1 reverse transcription, confirming the significance of their interaction in the virus
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Translation elongation is the stage of protein synthesis in which the translation factor eEF1A plays a pivotal role that is dependent on GTP exchange. In vertebrates, eEF1A can exist as two separately encoded tissue-specific isoforms, eEF1A1, which is almost ubiquitously expressed, and eEF1A2, which is confined to neurons and muscle. The GTP exchange factor for eEF1A1 is a complex called eEF1B made up of subunits eEF1Bα, eEF1Bδ and eEF1Bγ.

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Translation elongation factor eEF1A has a well-defined role in protein synthesis. In this study, we demonstrate a new role for eEF1A: it participates in the entire process of the heat shock response (HSR) in mammalian cells from transcription through translation. Upon stress, isoform 1 of eEF1A rapidly activates transcription of HSP70 by recruiting the master regulator HSF1 to its promoter.

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Translation elongation factor 1A2 (eEF1A2), uniquely among translation factors, is expressed specifically in neurons and muscle. eEF1A2-null mutant wasted mice develop an aggressive, early-onset form of neurodegeneration, but it is unknown whether the wasting results from denervation of the muscles, or whether the mice have a primary myopathy resulting from loss of translation activity in muscle. We set out to establish the relative contributions of loss of eEF1A2 in the different tissues to this postnatal lethal phenotype.

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This article was reviewed by Frank Eisenhaber and Ramanathan Sowdhamini.Translation elongation factors eEF1A1 and eEF1A2 are 92% identical but exhibit non-overlapping expression patterns. While the two proteins are predicted to have similar tertiary structures, it is notable that the minor variations between their sequences are highly localised within their modelled structures.

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The prokaryotic translation elongation factors were identified as essential cofactors for RNA-dependent RNA polymerase activity of the bacteriophage Qβ more than 40 years ago. A growing body of evidence now shows that eukaryotic translation elongation factors (eEFs), predominantly eEF1A, acting in partially characterized complexes sometimes involving additional eEFs, facilitate virus replication. The functions of eEF1A as a protein chaperone and an RNA- and actin-binding protein enable its "moonlighting" roles as a virus replication cofactor.

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Translation elongation factor isoform eEF1A2 is expressed in muscle and neurons. Deletion of eEF1A2 in mice gives rise to the neurodegenerative phenotype "wasted" (wst). Mice homozygous for the wasted mutation die of muscle wasting and neurodegeneration at four weeks post-natal.

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Cellular proteins have been implicated as important for HIV-1 reverse transcription, but whether any are reverse transcription complex (RTC) cofactors or affect reverse transcription indirectly is unclear. Here we used protein fractionation combined with an endogenous reverse transcription assay to identify cellular proteins that stimulated late steps of reverse transcription in vitro. We identified 25 cellular proteins in an active protein fraction, and here we show that the eEF1A and eEF1G subunits of eukaryotic elongation factor 1 (eEF1) are important components of the HIV-1 RTC.

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Translation elongation isoform eEF1A1 has a pivotal role in protein synthesis and is almost ubiquitously expressed. In mice and rats that transcription of the gene encoding eEF1A1 is downregulated to undetectable levels in muscle after weaning; eEF1A1 is then replaced by a separately encoded but closely related isoform eEF1A2, which has only previously been described in mammals. We now show that not only is eEF1A2 conserved in non-mammalian vertebrate species, but the down-regulation of eEF1A1 protein in muscle is preserved in Xenopus, with the protein being undetectable by adulthood.

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