Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Découverte d'un femur court à l'échographie du troisième trimestre de la grossesse : quelle conduite à tenir ?

REIMS-BU Santé (514542104) / SudocSudocFranceF

Mid- to Late Holocene shoreline reconstruction and human occupation in Ancient Eretria (South Central Euboea, Greece)

International audienceFew studies have aimed to reconstruct landscape change in the area of Eretria (South Central Euboea, Greece) during the last 6000 years. The aim of this paper is to partially fill in this gap by examining the interaction between Mid- to Late Holocene shoreline evolution and human occupation, which is documented in the area from the Late Neolithic to the Late Roman period (with discontinuities). Evidence of shoreline displacements is derived from the study of five boreholes (maximum depth of 5.25 m below the surface) drilled in the lowlands of Eretria. Based on sedimentological analyses and micro/macrofaunal identifications, different facies have been identified in the cores and which reveal typical features of deltaic progradation with marine, lagoonal, fluvio-deltaic and fluvial environments. In addition, a chronostratigraphy has been obtained based on 20 AMS 14C radiocarbon dates performed on samples of plant remains and marine/lagoonal shells found in situ. The main sequences of landscape reconstruction in the plain of Eretria can be summarized as follows: a marine environment predominated from ca. 4000 to 3200 cal. BC and a gradual transition to shallow marine conditions is observed ca. 3200-3000 cal. BC due to the general context of deltaic progradation west of the ancient city. Subsequently, from ca. 3000 to 2000 cal. BC, a lagoon occupied the area in the vicinity of the Temple of Apollo and the settlement's development was restricted to several fluvio-deltaic levees, thus severely limiting human activities in the plain. From ca. 2000 to 800 cal. BC, a phase of shallow marine presence prevailed and constrained settlement on higher ground, forcing abandonment of the major part of the plain. Finally, since the eighth century BC, the sea has regressed southward and created the modern landscape

Biotrophic transportome in mutualistic plant-fungal interactions

International audienceUnderstanding the mechanisms that underlie nutrient use efficiency and carbon allocation along with mycorrhizal interactions is critical for managing croplands and forests soundly. Indeed, nutrient availability, uptake and exchange in biotrophic interactions drive plant growth and modulate biomass allocation. These parameters are crucial for plant yield, a major issue in the context of high biomass production. Transport processes across the polarized membrane interfaces are of major importance in the functioning of the established mycorrhizal association as the symbiotic relationship is based on a 'fair trade' between the fungus and the host plant. Nutrient and/or metabolite uptake and exchanges, at biotrophic interfaces, are controlled by membrane transporters whose regulation patterns are essential for determining the outcome of plant-fungus interactions and adapting to changes in soil nutrient quantity and/or quality. In the present review, we summarize the current state of the art regarding transport systems in the two major forms of mycorrhiza, namely ecto- and arbuscular mycorrhiza

Prise en charge palliative des patients allogreffés : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

International audienceAllogeneic hematopoietic cell transplantation (allo-HCT), the only curative therapy for numerous hematological malignancies, carries a significant risk of morbidity and mortality. The patients and families’ expectations regarding the procedure, the prognosis uncertainties, as well as the existence of potential new therapeutic possibilities, lead to frequent use of intensive care. Even though the transplant physicians are highly skilled in acute care, their knowledge of palliative approach is limited, making the use of palliative care insufficient and often late. By promoting reflection on the proportionality of care and the patients’ quality of life, palliative care may contribute to the allo-HCT patients management. Nevertheless, obstacles to this approach remain. The objective of this work is to propose recommendations to promote the implementation of palliative care into transplant units.L’allogreffe de cellules hématopoïétiques, seule perspective curative pour certaines hémopathies malignes, comporte des risques de morbi-mortalité importants. Les attentes des patients et de leurs proches vis-à-vis de la procédure, les incertitudes pronostiques, ainsi que l’existence de nouvelles possibilités thérapeutiques, engendrent un recours fréquent, onéreux aux soins intensifs. Si les médecins greffeurs maîtrisent parfaitement les soins actifs, leur connaissance en ce qui concerne les soins palliatifs est limitée, rendant l’accès à ces soins très restreint et souvent tardif. Favorisant une réflexion sur la proportionnalité des soins et sur la qualité de vie des patients, les soins palliatifs peuvent contribuer à la prise en charge des patients allogreffés et à l’accompagnement de leurs proches. Néanmoins, des obstacles à cette approche demeurent. Cet article a pour objectif de proposer des recommandations pour favoriser l’intégration de la démarche palliative au sein des unités d’allogreffe

Inhibition of auxin signaling in Frankia species-infected cells in Casuarina glauca nodules leads to increased nodulation

Actinorhizal symbioses are mutualistic interactions between plants and the soil bacteria Frankia spp. that lead to the formation of nitrogen-fixing root nodules. The plant hormone auxin has been suggested to play a role in the mechanisms that control the establishment of this symbiosis in the actinorhizal tree Casuarina glauca. Here, we analyzed the role of auxin signaling in Frankia spp.-infected cells. Using a dominant-negative version of an endogenous auxin-signaling regulator, INDOLE-3-ACETIC ACID7, we established that inhibition of auxin signaling in these cells led to increased nodulation and, as a consequence, to higher nitrogen fixation per plant even if nitrogen fixation per nodule mass was similar to that in the wild type. Our results suggest that auxin signaling in Frankia spp.-infected cells is involved in the long-distance regulation of nodulation in actinorhizal symbioses

Molecular analysis and intestinal expression of <it>SAR1 </it>genes and proteins in Anderson's disease (Chylomicron retention disease)

<p>Abstract</p> <p>Background</p> <p>Anderson's disease (AD) or chylomicron retention disease (CMRD) is a very rare hereditary lipid malabsorption syndrome. In order to discover novel mutations in the <it>SAR1B </it>gene and to evaluate the expression, as compared to healthy subjects, of the Sar1 gene and protein paralogues in the intestine, we investigated three previously undescribed individuals with the disease.</p> <p>Methods</p> <p>The <it>SAR1B, SAR1A </it>and <it>PCSK9 </it>genes were sequenced. The expression of the <it>SAR1B </it>and <it>SAR1A </it>genes in intestinal biopsies of both normal individuals and patients was measured by RTqPCR. Immunohistochemistry using antibodies to recombinant Sar1 protein was used to evaluate the expression and localization of the Sar1 paralogues in the duodenal biopsies.</p> <p>Results</p> <p>Two patients had a novel <it>SAR1B </it>mutation (p.Asp48ThrfsX17). The third patient, who had a previously described <it>SAR1B </it>mutation (p.Leu28ArgfsX7), also had a p.Leu21dup variant of the <it>PCSK9 </it>gene. The expression of the <it>SAR1B </it>gene in duodenal biopsies from an AD/CMRD patient was significantly decreased whereas the expression of the <it>SAR1A </it>gene was significantly increased, as compared to healthy individuals. The Sar1 proteins were present in decreased amounts in enterocytes in duodenal biopsies from the patients as compared to those from healthy subjects.</p> <p>Conclusions</p> <p>Although the proteins encoded by the <it>SAR1A </it>and <it>SAR1B </it>genes are 90% identical, the increased expression of the <it>SAR1A </it>gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein. The PCSK9 variant, although reported to be associated with low levels of cholesterol, does not appear to exert any additional effect in this patient. The results provide further insight into the tissue-specific nature of AD/CMRD.</p

Identification of gene copy number variations in patients with mental retardation using array-CGH: Novel syndromes in a large French series.

International audienceArray-CGH has revealed a large number of copy number variations (CNVs) in patients with multiple congenital anomalies and/or mental retardation (MCA/MR). According to criteria recently listed, pathogenicity was clearly suspected for some CNVs but benign CNVs, considered as polymorphisms, have complicated the interpretation of the results. In this study, genomic DNAs from 132 French patients with unexplained mental retardation were analysed by genome wide high-resolution Agilent 44K oligonucleotide arrays. The results were in accordance with those observed in previous studies: the detection rate of pathogenic CNVs was 14.4%. A non-random involvement of several chromosomal regions was observed. Some of the microimbalances recurrently involved regions (1q21.1, 2q23.1, 2q32q33, 7p13, 17p13.3, 17p11.2, 17q21.31) corresponding to known or novel syndromes. For all the pathogenic CNVs, further cases are needed to allow more accurate genotype-phenotype correlations underscoring the importance of databases to group patients with similar molecular data