Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1. yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS

Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

Gemini MCAO Control System

The Gemini Observatory is planning to implement a Multi Conjugate Adaptive Optics System as a facility instrument for the Gemini-South telescope. The system will include 5 Laser Guide Stars, 3 Natural Guide Stars, and 3 Deformable mirrors optically conjugated at different altitudes to achieve near-uniform atmospheric compensation over a 1 arc minute square field of view. The control of such a system will be split in 3 main functions: the control of the opto-mechanical assemblies of the whole system (including the Laser, the Beam Transfer Optics and the Adaptive Optics bench), the control of the Adaptive Optics System itself at a rate of 800 frames per second and the control of the safety system. The control of the adaptive Optics System is the most critical in terms of real time performance. In this paper, we will describe the requirements for the whole Multi Conjugate Adaptive Optics Control System, preliminary designs for the control of the opto-mechanical devices and architecture options for the control of the Adaptive Optics system and the safety system

Biomarqueurs de toxicité et anomalies métaboliques dans les principales intoxications graves. Symptomatologie clinique et toxique. Le prélèvement conservatoire.

Les membres du groupe de travail pluridisciplinaire « Toxicologie et biologie clinique » appartenant à la Société française de biologie clinique (SFBC), à la Société française de toxicologie analytique (SFTA), à la Société de toxicologie clinique (STC), proposent une aide méthodologique à l’intention des biologistes non spécialistes en toxicologie. Ils formulent également pour respecter les bonnes pratiques de laboratoire un certain nombre de recommandations. Trois documents de synthèse ont été élaborés. Ils concernent d’une part, les biomarqueurs de toxicité et les anomalies métaboliques dans les principales intoxications graves et, d’autre part, les symptômes cliniques essentiels correspondant à ces intoxications, enfin des recommandations sur le prélèvement conservatoire. Pour les biomarqueurs de toxicité, le tableau de synthèse concerne une cinquantaine de xénobiotiques : les principaux symptômes, les méthodes d’identification ou de dosage disponibles en urgence, les marqueurs biologiques utiles, la décision clinique correspondante, les dosages éventuels nécessaires à la prise en charge du patient, ainsi que l’antidote lorsque celui-ci existe. En ce qui concerne les techniques, le groupe propose un certain nombre de recommandations relatives au domaine clinique et médico-légal. Le groupe insiste également sur la nécessité de procéder dans certains cas à des prélèvements biologiques conservatoires dès la prise en charge du malade, prélèvements qui seront ou ne seront pas analysés en fonction du contexte et/ou de l’évolution de l’intoxication

Initial Steroid Sensitivity in Children with Steroid-Resistant Nephrotic Syndrome Predicts Post-Transplant Recurrence

Of children with idiopathic nephrotic syndrome, 10%–20% fail to respond to steroids or develop secondary steroid resistance (termed initial steroid sensitivity) and the majority progress to transplantation. Although 30%–50% of these patients suffer disease recurrence after transplantation, with poor long-term outcome, no reliable indicator of recurrence has yet been identified. Notably, the incidence of recurrence after transplantation appears reduced in patients with steroid-resistant nephrotic syndrome (SRNS) due to monogenic disorders. We reviewed 150 transplanted patients with SRNS to identify biomarkers that consistently predict outcome of SRNS after transplantation. In all, 25 children had genetic or familial SRNS and did not experience post-transplant recurrence. We reviewed phenotypic factors, including initial steroid sensitivity, donor type, age, ethnicity, time to ESRD, and time on dialysis, in the remaining 125 children. Of these patients, 57 (45.6%) developed post-transplant recurrence; 26 of 28 (92.9%) patients with initial steroid sensitivity recurred after transplantation, whereas only 26 of 86 (30.2%) patients resistant from the outset recurred (odds ratio, 30; 95% confidence interval, 6.62 to 135.86; P<0.001). We were unable to determine recurrence in two patients (one with initial steroid sensitivity), and nine patients did not receive initial steroids. Our data show that initial steroid sensitivity is highly predictive of post-transplant disease recurrence in this pediatric patient population. Because a pathogenic circulating permeability factor in nephrotic syndrome remains to be confirmed, we propose initial steroid sensitivity as a surrogate marker for post-transplant recurrence

Generating genomic platforms to study Candida albicans pathogenesis

The advent of the genomic era has made elucidating gene function on a large scale a pressing challenge. ORFeome collections, whereby almost all ORFs of a given species are cloned and can be subsequently leveraged in multiple functional genomic approaches, represent valuable resources toward this endeavor. Here we provide novel, genome-scale tools for the study of Candida albicans, a commensal yeast that is also responsible for frequent superficial and disseminated infections in humans. We have generated an ORFeome collection composed of 5099 ORFs cloned in a Gateway™ donor vector, representing 83% of the currently annotated coding sequences of C. albicans. Sequencing data of the cloned ORFs are available in the CandidaOrfDB database at http://candidaorfeome.eu. We also engineered 49 expression vectors with a choice of promoters, tags and selection markers and demonstrated their applicability to the study of target ORFs transferred from the C. albicans ORFeome. In addition, the use of the ORFeome in the detection of protein-protein interaction was demonstrated. Mating-compatible strains as well as Gateway™-compatible two-hybrid vectors were engineered, validated and used in a proof of concept experiment. These unique and valuable resources should greatly facilitate future functional studies in C. albicans and the elucidation of mechanisms that underlie its pathogenicity.status: publishe

Generating genomic platforms to study Candida albicans pathogenesis

The advent of the genomic era has made elucidating gene function on a large scale a pressing challenge. ORFeome collections, whereby almost all ORFs of a given species are cloned and can be subsequently leveraged in multiple functional genomic approaches, represent valuable resources toward this endeavor. Here we provide novel, genome-scale tools for the study of Candida albicans, a commensal yeast that is also responsible for frequent superficial and disseminated infections in humans. We have generated an ORFeome collection composed of 5099 ORFs cloned in a Gateway (TM) donor vector, representing 83% of the currently annotated coding sequences of C. albicans. Sequencing data of the cloned ORFs are available in the CandidaOrfDB database at http://candidaorfeome.eu. We also engineered 49 expression vectors with a choice of promoters, tags and selection markers and demonstrated their applicability to the study of target ORFs transferred from the C. albicans ORFeome. In addition, the use of the ORFeome in the detection of protein-protein interaction was demonstrated. Mating-compatible strains as well as Gateway (TM)-compatible two-hybrid vectors were engineered, validated and used in a proof of concept experiment. These unique and valuable resources should greatly facilitate future functional studies in C. albicans and the elucidation of mechanisms that underlie its pathogenicity