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Gemistocytic astrocytoma (World Health Organization grade II) is a rare variant of diffuse astrocytoma that is characterized by the presence of neoplastic gemistocytes and has a significantly less favorable prognosis. Other than frequent TP53 mutations (>80%), little is known about its molecular profile. Here, we show that gemistocytic astrocytomas carry a lower frequency of IDH mutations than fibrillary astrocytomas (74% vs 92%; p = 0.0255) but have profiles similar to those of fibrillary astrocytomas with respect to TERT promoter mutations (5% vs 0%), 1p/19q loss (10% vs 8%), and loss of heterozygosity 10q (10% vs 12%). Exome sequencing in 5 gemistocytic astrocytomas revealed homozygous deletion of genes at 19q13 (i.e. RRAS [related RAS viral oncogene homolog; 2 cases] and ERCC1 [excision repair cross-complementing rodent repair deficiency, complementation group 1; 1 case]). Further screening showed RRAS homozygous deletion in 7 of 42 (17%) gemistocytic astrocytomas and in 3 of 24 (13%) IDH1 mutated secondary glioblastomas. Patients with gemistocytic astrocytoma and secondary glioblastoma with an RRAS deletion tended to have shorter survival rates than those without deletion. Differential polymerase chain reaction and methylation-specific polymerase chain reaction revealed an ERCC1 homozygous deletion or promoter methylation in 10 of 42 (24%) gemistocytic astrocytomas and in 8 of 24 (33%) secondary glioblastomas. Alterations in RRAS and ERCC1 appear to be typical in gemistocytic astrocytomas and secondary glioblastomas, since they were not present in 49 fibrillary astrocytomas or 30 primary glioblastomas.

Background: Hantaviruses are single-stranded RNA viruses, which are transmitted to humans primarily via inhalation of aerosolised virus in contaminated rodent urine and faeces. Whilst infected reservoir hosts are asymptomatic, human infections can lead to two clinical manifestations, haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), with varying degrees of clinical severity. The incidence of rodent and human cases of Seoul virus (SEOV) in Europe has been considered to be low, and speculated to be driven by the sporadic introduction of infected brown rats (Rattus norvegicus) via ports., Methods: Between October 2010 and March 2012, 128 brown rats were caught at sites across the Lyon region in France., Results: SEOV RNA was detected in the lungs of 14% (95% CI 8.01-20.11) of brown rats tested using a nested pan-hantavirus RT-PCR (polymerase gene). Phylogenetic analysis supports the inclusion of the Lyon SEOV within Lineage 7 with SEOV strains originating from SE Asia and the previously reported French & Belgian SEOV strains. Sequence data obtained from the recent human SEOV case (Replonges) was most similar to that obtained from one brown rat trapped in a public park in Lyon city centre. We obtained significantly improved recovery of virus genome sequence directly from SEOV infected lung material using a simple viral enrichment approach and NGS technology., Conclusions: The detection of SEOV in two wild caught brown rats in the UK and the multiple detection of SEOV infected brown rats in the Lyon region of France, suggests that SEOV is circulating in European brown rats. Under-reporting and difficulties in identifying the hantaviruses associated with HFRS may mask the public health impact of SEOV in Europe.

To improve our understanding of the molecular events underlying the effects of positive allosteric modulators of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (S)-AMPA-type glutamate receptors, gene expression profiles of primary cortical culture were measured by Agilent-Microarray technique under (S)-AMPA (1μM) stimulation for 0.5, 6, 24 and 48h in the presence or absence of S70340 (30μM), an allosteric potentiator of AMPA receptors. (S)-AMPA and S70340 treatment alone have little effect on gene expression whereas as early as 6h, their combination induced a large number of genes known to decrease apoptosis and mediate cell survival. Pathway analyses of (S)-AMPA+S70340 treatment-mediated gene expression from 6 to 48h further suggested the activation of cellular functions including neuron differentiation and neurite outgrowth. A proportion of genes implicated in these functions encode proteins involved in environmental cues and are expressed in growth cones, such as extracellular matrix component proteins and filopodia microfilament-associated proteins. Time course analysis of mRNA expression combined with in silico promoter analysis revealed an enrichment in the cAMP response element (CRE) among co-regulated genes. This study demonstrated that S70340-mediated AMPA potentialisation activated genes and functional processes involved in neuroprotective and cognitive effects and describes putative new functional biomarkers., (Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Patients carrying mutations in the retinal guanylate cyclase (GUCY2D) gene were reported to be constantly affected with a particular form of Leber congenital amaurosis (LCA) defined as a "congenital stationary cone-rod dystrophy with high hypermetropia, panretinal degeneration and highly reduced visual acuity". We report here, the study of two patients affected with different retinal disorder: a typical GUCY2D-LCA phenotype and early-onset severe retinitis pigmentosa (RP). Unexpectedly, they gave birth to an infant suffering from LCA. The genetic study in the family allowed to explain the disease in the infant by showing that the GUCY2D-LCA disease was accounted for by compound heterozygosity for two severe GUCY2D mutations (c.3043+4A>T, c.2943delG) while the early-onset severe RP resulted from homozygosity for a 4 bp insertion in the same gene, despite the sound phenotypic differences (c.3236insACCA). Interestingly, this last mutation is excepted to result in a 28 amino acid elongation of the protein contrary to all GUCY2D mutations accounting for LCA which are expected to be null alleles. This report gives support to the existence of exceptional GUCY2D mutations accounting for a milder and different phenotype compared to the typical GUCY2D congenital stationary cone-rod dystrophy., ((c) 2005 Wiley-Liss, Inc.)

Leber congenital amaurosis (LCA), the most early-onset and severe form of all inherited retinal dystrophies, is responsible for congenital blindness. Ten LCA genes have been mapped, and seven of these have been identified. Because some of these genes are involved in the visual cycle, we regarded the retinal pigment epithelium and photoreceptor-specific retinal dehydrogenase (RDH) genes as candidate genes in LCA. Studying a series of 110 unrelated patients with LCA, we found mutations in the photoreceptor-specific RDH12 gene in a significant subset of patients (4.1%). Interestingly, all patients harboring RDH12 mutations had a severe yet progressive rod-cone dystrophy with severe macular atrophy but no or mild hyperopia.

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium but they are involved in strikingly different physiologic pathways resulting in an unforeseeable physiopathologic variety. This wide genetic and physiologic heterogeneity that could largely increase in the coming years, hinders the molecular diagnosis in LCA patients. The genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here, we report a comprehensive mutational analysis of the all known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% patients. GUCY2D appeared to account for most LCA cases of our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%), and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited to search for phenotype variations. Sound genotype-phenotype correlations were found that allowed us to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, while the second group gathers patients affected with severe yet progressive rod-cone dystrophy. Besides, objective ophthalmologic data allowed us to subdivide each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the heavy task of genotyping new patients but only if one has access to the most precise clinical history since birth., (Copyright 2004 Wiley-Liss, Inc.)

In contrast to the frequent dominant optic atrophies (DOAs) in which the neuropathy is usually an isolated event, isolated recessive optic atrophies (ROAs) are very uncommon and have been described as severe congenital or early infantile conditions. To date, two loci for isolated DOA have been mapped, of which one was ascribed to mutations in the OPA1 gene. Conversely, no isolated autosomal ROA locus had previously been localised. Here, we report a large multiplex consanguineous family of French origin affected with an early onset but slowly progressive form of isolated OA. A genome-wide search for homozygosity allowed the localisation of the disease-causing gene to chromosome 8q21-q22 (Zmax of 3.41 at theta=0 for D8S270), in a 12 Mb interval flanked by markers D8S1702 and D8S1794. This localisation excludes allelism of the disease with both isolated DOAs, on one hand, or all known syndromic forms of ROA, on the other hand, supporting the mapping of a first gene for isolated autosomal ROA (ROA1) on the long arm of chromosome 8.

Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal recessive condition responsible for congenital blindness or greatly impaired vision since birth. Eight LCA loci have been mapped, but only six out of eight genes have been hitherto identified. A genome-wide screen for homozygosity was conducted in a large consanguineous family originating from Palestine, for which no mutation was found in any of the six known LCA genes and that excluded the LCA3 and LCA5 loci. Evidence for homozygosity, however, was found in all affected patients of the family on chromosome 1q31, a region in which the human homologue of the Drosophila melanogaster crumbs gene (CRB1) has been mapped. Consequently, we proposed a hypothesis that the disease-causing mutation in this family might lie in an unexplored region of this LCA gene. As a matter of fact, while no mutation was found in any of the 11 CRB1 exons originally reported, we identified a 10-bp (del 4121-4130) deletion segregating with the disease in a later reported 12th exon lying in the 3' end of the gene. Interestingly, this deletion disrupts an amino acid sequence that was shown to be crucial for the function of the protein in the Drosophila counterpart (CRB).

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies. It is a genetically heterogeneous condition as six disease-causing genes have been hitherto identified. Among them, RETGC1 (GUCY2D), is more frequently implicated in our series of LCA patients. Interestingly, 70 % of the families with RETGC1 mutations are originating from Mediterranean countries, the remaining families (30%) being originating from various countries across the world. Here, we report, the identification of the same homozygous RETGC1 nonsense mutation in three unrelated and non-consanguineous LCA families of Finnish origin, suggesting a founder effect. Interestingly, no linkage desequilibrium was found using polymorphic markers flanking the RETGC1 gene, supporting the view that the mutation is very ancient. Haplotype studies and Bayesian calculation point the founder mutation to 150 generations (95% credible interval 80-240 generations), i.e., 3000 years ago., (Copyright 2002 Wiley-Liss, Inc.)

Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal recessive condition responsible for congenital blindness or greatly impaired vision since birth. So far, six LCA loci have been mapped but only 4 out of 6 genes have been identified. A genome-wide screen for homozygosity was conducted in seven consanguineous families unlinked to any of the six LCA loci. Evidence for homozygosity was found in two of these seven families at the 14q11 chromosomal region. Two retinal specific candidate genes were known to map to this region, namely the neural retina leucine zipper (NRL) and the retinitis pigmentosa GTPase regulator interacting protein (RPGRIP1). No mutation of the NRL gene was found in any of the two families. Thus, we determined the complete exon-intron structure of the RPGRIP1 gene. RPGRIP1 encompasses 24 coding exons, nine of which are first described here with their corresponding exon-intron boundaries. The screening of the gene in the two families consistent with linkage to chromosome 14q11 allowed the identification of a homozygous null mutation and a homozygous missense mutation, respectively. Further screening of LCA patients unlinked to any of the four already identified LCA genes (n=86) identified seven additional mutations in six of them. In total, eight distinct mutations (5 out of 8 truncating) in 8/93 patients were found. So far this gene accounts for eight out of 142 LCA cases in our series (5.6%).

Purpose: Leber congenital amaurosis (LCA) is the earliest and the most severe form of all inherited retinal dystrophies. In 1996, the current investigators ascribed the disease in families linked to the LCA1 locus on chromosome 17p13.1 to mutations in the photoreceptor-specific guanylyl cyclase (retGC-1) gene. So far, 22 different mutations, of which 11 are missense mutations, have been identified in 25 unrelated families. This is a report of the functional analyses of nine of the missense mutations., Methods: cDNA constructs were generated that contained the retGC-1 missense mutations identified in patients related to the LCA1 locus. Mutants were expressed in COS7 cells and assayed for their ability to hydrolyze guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP)., Results: All mutations lying in the catalytic domain showed a complete abolition of cyclase activity. In contrast, only one mutation lying in the extracellular domain also resulted in a severely reduced catalytic activity, whereas the others showed completely normal activity., Conclusions: More than half the mutations identified in patients related to the LCA1 locus are truncating mutations expected to result in a total abolition of retGC-1 activity. Concerning missense mutations, half of them lying in the catalytic domain of the protein also result in the complete inability of the mutant cyclases to hydrolyze GTP into cGMP in vitro. In contrast, missense mutations lying in the extracellular domain, except one affecting the initiation codon, showed normal catalytic activity of retGC-1. Nevertheless, considering that all patients related to the LCA1 locus displayed the same phenotype, it can be assumed that all missense mutations would have the same dramatic consequences on protein activity in vivo as truncation mutations.