Source X par agrégats : contrôle et optimisation des paramètres gouvernant línteraction laser de puissance - agrégats de gaz rare

National audienceLes expériences que nous avons réalisées sur le Laser Ultra Court Accordable du CEA Saclay permettent dóbserver l\'émission de photons X dans la gamme 1-5 keV lors de lírradiation dágrégats de gaz rare (Ar, Kr et Xe comprenant entre 10^3 et 10^6 atomes par agrégat) avec un laser femtoseconde de puissance (Ipic jusqu\'à 10^17 W/cm²). En plus de la distribution des états de charge des ions responsables de l\'émission X, la technique de spectroscopie X que nous utilisons permet de mesurer les taux absolus de photons émis dans 4π par impulsion laser en fonction des paramètres gouvernant línteraction dans des conditions contrôlées. Nous avons déterminé la sensibilité des paramètres physiques régissant la production du rayonnement X pendant línteraction, ce qui permet dáccéder à lóptimisation de cette source. Cet article est plus particulièrement dédié aux résultas relatifs à l\'évolution du taux d\'X avec l\'éclairement laser, dúne part, et avec la durée de límpulsion laser, dáutre part

Émission X(L) du xénon par interaction laser -agrégats

National audienceNous avons étudié le rayonnement X provenant d'ions fortement multichargés (" 24+) présentant des lacunes en couche L produits lors de l'irradiation d'agrégats de xénon par des impulsions lumineuses issues d'un laser femtoseconde de puissance. Les résultats obtenus lors de la toute dernière campagne d'expériences réalisée auprès du serveur LUCA du SPAM/DRECAM au CEA/Saclay mettent en cause certains travaux antérieurs. Des divergences marquées apparaissent tant au niveau de l'interprétation des spectres X que sur la variation du taux d'émission en fonction de l'éclairement et de la longueur d'onde

Dynamique sub-picoseconde de l'interaction laser de puissance – agrégats de gaz rare : émission intense de rayons X et production d'ions multichargés.

National audienceLors de campagnes d'expériences réalisées sur le Laser Ultra Court Accordable du CEA/Saclay, nous avons étudié le rayonnement X, tant qualitativement (spectroscopie et énergie moyenne des photons) que quantitativement (taux absolus et lois d'évolution), émis lors de l'interaction d'un jet effusif d'agrégats de gaz rare (Ar, Kr, Xe comprenant entre 10^4 et 10^6 atomes/agrégat) avec un laser femtoseconde de puissance (éclairement jusqu'à quelques 10^17 W/cm2). Les résultats présentés dans ce manuscrit sont uniquement dédiés aux agrégats d'Ar pour lesquels nous avons observé un rayonnement X issu d'ions fortement multichargés (jusqu'à l'Ar16+) présentant des lacunes en couches K. La technique de spectroscopie X utilisée a permis de déterminer pour la première fois des taux absolus ainsi que les lois d'évolution de l'émission X en fonction de l'ensemble des paramètres gouvernant l'interaction (intensité, polarisation, longueur d'onde et durée du pulse laser aussi bien que taille, densité et numéro atomique des agrégats)

Loss of function of RIMS2 causes a syndromic congenital cone-rod synaptic disease with neurodevelopmental and pancreatic involvement

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD

Submicroscopic Deletions at 13q32.1 Cause Congenital Microcoria.

International audienceCongenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR

Leber Congenital Amaurosis: Comprehensive Survey of the Genetic Heterogeneity, Refinement of the Clinical Definition, and Genotype-Phenotype Correlations as a Strategy for Molecular Diagnosis

Communicated by Jean-Claude Kaplan 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 rodcone 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

IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype

Background: Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. Methods: We screened 1628 individuals with reno-ocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. Results: Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. Conclusions: This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development

rs5888 Variant of SCARB1 Gene Is a Possible Susceptibility Factor for Age-Related Macular Degeneration

Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors, including variants in the CFH gene and the ARMS2 LOC387715/HTRA1locus. Our purpose was to perform a case-control study in two populations among individuals who did not carry risk variants for CFHY402H and LOC387715 A69S (ARMS2), called “study” individuals, in order to identify new genetic risk factors. Based on a candidate gene approach, we analyzed SNP rs5888 of the SCARB1 gene, coding for SRBI, which is involved in the lipid and lutein pathways. This study was conducted in a French series of 1241 AMD patients and 297 controls, and in a North American series of 1257 patients with advanced AMD and 1732 controls. Among these individuals, we identified 61 French patients, 77 French controls, 85 North American patients and 338 North American controls who did not carry the CFH nor ARMS2 polymorphisms. An association between AMD and the SCARB1 gene was seen among the study subjects. The genotypic distribution of the rs5888 polymorphism was significantly different between cases and controls in the French population (p<0.006). Heterozygosity at the rs5888 SNP increased risk of AMD compared to the CC genotypes in the French study population (odds ratio (OR) = 3.5, CI95%: 1.4–8.9, p<0.01) and after pooling the 2 populations (OR = 2.9, 95% CI: 1.6–5.3, p<0.002). Subgroup analysis in exudative forms of AMD revealed a pooled OR of 3.6 for individuals heterozygous for rs5888 (95% CI: 1.7–7.6, p<0.0015). These results suggest the possible contribution of SCARB1, a new genetic factor in AMD, and implicate a role for cholesterol and antioxidant micronutrient (lutein and vitamin E) metabolism in AMD