Differential co-assembly of α1-GABAARs associated with epileptic encephalopathy

GABAA receptors (GABAARs) are profoundly important for controlling neuronal excitability. Spontaneous and familial mutations to these receptors feature prominently in excitability disorders and neurodevelopmental deficits following disruption to GABA-mediated inhibition. Recent genotyping of an individual with severe epilepsy and Williams-Beuren Syndrome identified a frameshifting de novo variant in a major GABAAR gene, GABRA1. This truncated the α1 subunit between the third and fourth transmembrane domains and introduced 24 new residues forming the mature protein, α1Lys374Serfs*25 Cell surface expression of mutant murine GABAARs is severely impaired compared to wild-type, due to retention in the endoplasmic reticulum. Mutant receptors were differentially co-expressed with β3, but not with β2 subunits in mammalian cells. Reduced surface expression was reflected by smaller inhibitory postsynaptic currents, which may underlie the induction of seizures. The mutant does not have a dominant negative effect on native neuronal GABAAR expression since GABA current density was unaffected in hippocampal neurons, even though mutant receptors exhibited limited GABA sensitivity. To date, the underlying mechanism is unique for epileptogenic variants and involves differential β subunit expression of GABAAR populations, which profoundly affected receptor function and synaptic inhibition.SIGNIFICANCE STATEMENTGABAARs are critical for controlling neural network excitability. They are ubiquitously distributed throughout the brain and their dysfunction underlies many neurological disorders, especially epilepsy. Here we report the characterisation of an α1-GABAAR variant that results in severe epilepsy. The underlying mechanism is structurally unusual, with the loss of part of the α1 subunit transmembrane domain and part-replacement with nonsense residues. This led to compromised and differential α1-subunit cell surface expression with β subunits resulting in severely reduced synaptic inhibition. Our study reveals that disease-inducing variants can affect GABAAR structure, and consequently subunit assembly and cell surface expression, critically impacting on the efficacy of synaptic inhibition, a property that will orchestrate the extent and duration of neuronal excitability

Validating the Cognitive Scale for Down Syndrome (CS-DS) to Detect Longitudinal Cognitive Decline in Adults With Down Syndrome

Down syndrome (DS) is associated with intellectual disability and an ultra-high risk of developing dementia. Informant ratings are invaluable to assess abilities and related changes in adults with DS, particularly for those with more severe intellectual disabilities and/or cognitive decline. We previously developed the informant rated Cognitive Scale for Down Syndrome (CS-DS) to measure everyday cognitive abilities across memory, executive function, and language domains in adults with DS, finding CS-DS scores are a valid measure of general abilities, and are significantly lower for those with noticeable cognitive decline compared to those without decline. To further test the validity of the CS-DS in detecting changes associated with cognitive decline we collected longitudinal data across two time points, approximately 1.5–2 years apart, for 48 adults with DS aged 36 years and over. CS-DS total scores (78.83 ± 23.85 vs. 73.83 ± 25.35, p = 0.042) and executive function scores (46.40 ± 13.59 vs. 43.54 ± 13.60, p = 0.048) significantly decreased between the two time points, with scores in the memory domain trending towards a significant decrease (22.19 ± 8.03 vs. 20.81 ± 8.63, p = 0.064). Adults with noticeable cognitive decline at follow-up showed a trend to significantly greater change in total scores (7.81 ± 16.41 vs. 3.59 ± 16.79, p = 0.067) and significantly greater change in executive function scores (5.13 ± 9.22 vs. 1.72 ± 9.97, p = 0.028) compared to those without decline. Change in total scores showed significant correlations with change in scores from other informant measures of everyday adaptive abilities and symptoms associated with dementia, and participant assessment of general cognitive abilities (all p < 0.005), while change in memory scores (R2 = 0.28, p = 0.001) better predicted change in participant cognitive assessment scores than change in executive function (R2 = 0.15, p = 0.016) or language (R2 = 0.15, p = 0.018) scores. These results suggest informants may better detect changes in the executive function domain, while change in informant rated memory scores best predicts change in assessed cognitive ability. Alternatively, memory domain scores may be sensitive to changes across both early and late cognitive decline, whereas executive function domain scores are more sensitive to changes associated with later noticeable cognitive decline. Our results provide further support for the validity of the CS-DS to assess everyday cognitive abilities and to detect associated longitudinal changes in individuals with DS

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Down syndrome, caused by an extra copy of chromosome 21, is associated with a greatly increased risk of early onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP), an Alzheimer risk factor, although the possession of extra copies of other chromosome 21 genes may also play a role. Further study of the mechanisms underlying the development of Alzheimer disease in Down syndrome could provide insights into the mechanisms that cause dementia in the general population

A simplified analytical approach for evaluation of the optimal ratio of pressure drop across the turbine in solar chimney power plants

In this paper, a simplified analytical approach for evaluating the factor of turbine pressure drop in solar chimney power plants is presented. This characteristic factor (or pressure drop ratio in turbines, according to the total pressure drop in the chimney) is important because it is related to the output power. The determined factor (or ratio) values of the turbine pressure drop are found to be within a value range consistent with other studies. It was concluded that for solar chimney power plants, turbine pressure drop factors are in the range of 0.8-0.9. This simplified analytical approach is useful for preliminary analysis and fast evaluation of the potential of solar chimney power plants.Solar chimney Turbine pressure drop Overall efficiency

Choix des priorités et des Stratégies

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Evaluation des Programmes de Santé: Principes de Base.

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Model for a transcript map of human chromosome 21: isolation of new coding sequences from exon and enriched cDNA libraries.

The construction of a transcriptional map for human chromosome 21 requires the generation of a specific catalogue of genes, together with corresponding mapping information. Towards this goal, we conducted a pilot study on a pool of random chromosome 21 cosmids representing 2 Mb of non-contiguous DNA. Exon-amplification and cDNA selection methods were used in combination to extract the coding content from these cosmids, and to derive expressed sequences libraries. These libraries and the source cosmid library were arrayed at high density for hybridisation screening. A strategy was used which related data obtained by multiple hybridisations of clones originating from one library, screened against the other libraries. In this way, it was possible to integrate the information with the physical map and to compare the gene recovery rate of each technique. cDNAs and exons were grouped into bins delineated by EcoRI cosmid fragments, and a subset of 91 cDNAs and 29 exons have been sequenced. These sequences defined 79 non-overlapping potential coding segments distributed in 24 transcriptional units, which were mapped along 21q. Northern blot analysis performed for a subset of cDNAs indicated the existence of a cognate transcript. Comparison to databases indicated three segments matching to known chromosome 21 genes: PFKL, COL6A1 and S100B and six segments matching to unmapped anonymous expressed sequence tags (ESTs). At the translated nucleotide level, strong homologies to known proteins were found with ATP-binding transporters of the ABC family and the dihydroorotase domain of pyrimidine synthetases. These data strongly suggest that bona fide partial genes have been isolated. Several of the newly isolated transcriptional units map to clinically important regions, in particular those involved in Down's syndrome, progressive myoclonus epilepsia and auto-immune polyglandular disease. The study presented here illustrates the complementarity of exon-amplification and cDNA selection techniques for generating a large resource of new expressed landmarks, which contribute to the construction of a chromosome 21 transcript map

Differential Coassembly of alpha 1-GABA(A)Rs Associated with Epileptic Encephalopathy

GABAA receptors (GABAARs) are profoundly important for controlling neuronal excitability. Spontaneous and familial mutations to these receptors feature prominently in excitability disorders and neurodevelopmental deficits following disruption to GABA-mediated inhibition. Recent genotyping of an individual with severe epilepsy and Williams-Beuren syndrome identified a frameshifting de novo variant in a major GABAAR gene, GABRA1. This truncated the α1 subunit between the third and fourth transmembrane domains and introduced 24 new residues forming the mature protein, α1Lys374Serfs*25. Cell surface expression of mutant murine GABAARs is severely impaired compared with WT, due to retention in the endoplasmic reticulum. Mutant receptors were differentially coexpressed with β3, but not with β2, subunits in mammalian cells. Reduced surface expression was reflected by smaller IPSCs, which may underlie the induction of seizures. The mutant does not have a dominant-negative effect on native neuronal GABAAR expression since GABA current density was unaffected in hippocampal neurons, although mutant receptors exhibited limited GABA sensitivity. To date, the underlying mechanism is unique for epileptogenic variants and involves differential β subunit expression of GABAAR populations, which profoundly affected receptor function and synaptic inhibition.Ministry of Education (MOE)National Medical Research Council (NMRC)Published versionT.G.S. and S.H. were supported by Medical Research Council United Kingdom, Wellcome Trust, and International Rett Syndrome Foundation (3606). D.N. was supported by Singapore National Medical Research Council NMRC/CIRG/1438/2015, Singapore Ministry of Education Academic Research Fund Tier 2 Grant 2015-T2-1-023, and Wellcome Trust “LonDownS Consortium” Strategic Funding Award 098330/Z/12/Z. B.P. was supported by the Deutsche Forschungsgemeinschaft Grant PO2366/2-1