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. The remaining subunits of the eEF1 complex, eEF1Bα, eEF1Bδ, eEF1Bγ, and valyl‐tRNA synthetase (VARS), together form the GTP exchange factor for eEF1A and are ubiquitously expressed, in keeping with their housekeeping role. However, mutations in the genes encoding these subunits EEF1B2 (eEF1Bα), EEF1D (eEF1Bδ), and VARS (valyl‐tRNA synthetase) have also now been identified as causes of neurodevelopmental disorders. In this review, we describe the mutations identified so far in comparison with the degree of normal variation in each gene, and the predicted consequences of the mutations on the functions of the proteins and their isoforms. We discuss the likely effects of the mutations in the context of the role of protein synthesis in neuronal development.
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. We have used CRISPR/Cas9 gene editing in the mouse to mutate the gene encoding eEF1A2, obtaining a high frequency of biallelic mutations. Whilst many of the resulting founder (F0) mice developed motor neuron degeneration, others displayed phenotypes consistent with a severe neurodevelopmental disorder, including sudden unexplained deaths and audiogenic seizures. The presence of G70S protein was not sufficient to protect mice from neurodegeneration in G70S/− mice, showing that the mutant protein is essentially non-functional.
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. In order both to address this question and to provide a novel model for neurodevelopmental disorders resulting from mutations in EEF1A2, we created a new mouse model of the D252H mutation. This mutation causes the eEF1A2 protein to be expressed at lower levels in brain but higher in muscle in the mice. We compared both heterozygous and homozygous D252H and null mutant mice using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. Although the proteomic analysis pointed to a loss of function for the D252H mutant protein, the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. Mice that are heterozygous for the missense mutation show no behavioural abnormalities but do have sex-specific deficits in body mass and motor function. The phenotyping of our novel mouse lines, together with analysis of molecular modelling and interacting proteins, suggest that the D252H mutation results in a gain of function.
Background: Alterations in glycosylation patterns have long been known to reflect changes in cell metabolism. In this study, we investigated the relationship between human N-glycan profiles and metabolic syndrome. Method:Between 2005 and 2011, 2,155 individuals from the Orkney Islands (UK) were recruited and biological material, alongside phenotypic measures were collected. Individual N-glycan profiles were measured in plasma using weak anion exchange high performance liquid chromatography and calibrated hydrophilic interaction liquid chromatography. Pre-specified criteria were used to identify 564 cases with metabolic syndrome and 1475 controls. We applied logistic regression to test for association between this binary outcome against measured plasma N-glycans. We also assessed the correlation between N-glycan traits and individual components of metabolic syndrome and compared this to results found in similar analyses based in Chinese and Croatian populations.Results: 21 N-glycan traits were found to be associated with either an increased or a decreased likelihood of participants having metabolic syndrome, including monosialylated plasma N-glycans (OR of 1.49 (95%CI 1.33, 1.67), q=1.26E-12) and core fucosylated plasma N-glycans (OR of 0.81(95% CI 0.72-0.90), q=7.75E-4). Notably, consistent results in both sections of this analysis demonstrated the protective association of higher levels of core fucosylated N-glycans. Conclusion:Our results demonstrate that metabolic syndrome is associated with an alteration in plasma N-glycosylation patterns. The metabolic role of core fucosylated N-glycans is of particular interest for future study.
The paper draws on a recent research project 'Design at the Heart of Housebuilding', commissioned by the Scottish Government and undertaken in 2006-7; subsequently published in early 2008. This research focused on the conceptions and practice of design within private sector house developers in Scotland, which is used here as a basis for speculatively exploring opposing values between private sector housing developers and architects in housing design. Drawing initially on reviews of this relationship in the initial mass private sector housing provision in the inter-war period in the UK the paper then compares this with the more recent position as evidenced in the research, two generations later. It identifies and analyses the basis for a perpetuated mutual wariness as a way to understand the potential for change in current trends, and ends by highlighting some examples of alternative collaborations, where the skills and values of architects are more fully articulated with those of developers and manufacturers in innovative housing provision, including forms of mass customisation.
This article examines the role of colour as an integral consideration of material selection. It suggests that an understanding of colour, and its potential to alter the general perception of form, space and surface, is as essential as any other material property. Recent developments have led to a period of growth in the use of colour in architectural design, for example through highly pigmented ceramic tiles, back-painted glass facades and pigmented concrete. These offer permanent and durable surfaces. The potential of colour to alter the perception of space and form brings with it a certain anxiety in its use, particularly when embedded on the exterior surfaces of buildings. Yet decisions on colour are often arbitrary and left until late in the design process. The article will consider colour and material surface, colour as conceptual material, the elusive properties of colour, which are entirely contingent on light conditions and context, and colour specification in the design process.
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