De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10−11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10−15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease

Solvants eutectiques profonds - Vers des procédés plus durables

Deep eutectic solvents are a new class of solvents that appeared in the early 2000s. They are prepared by mixing two or more compounds and in general present a low environmental impact. In this article, we present the evolution of the still controversial definition of a deep eutectic solvent. Furthermore, the properties of these solvents are discussed and several potential applications are presented. Notably, their applications in electrochemical processes, in extraction and purification, as well as in reaction media or for the solubilization of gases or volatile organic compounds are considered. Their advantages as well as their limitations are examined.Les solvants eutectiques profonds sont une nouvelle classe de solvants apparue au début des années 2000. Ils sont obtenus par le mélange de deux ou de plusieurs composés et présentent en général un faible impact environnemental. Dans cet article, l’évolution de la définition d’un solvant eutectique profond est présentée, celle-ci n’étant toujours pas arrêtée précisément. Les propriétés de ces solvants sont exposées et leurs applications potentielles dans des procédés d’électrochimie, l’extraction et la purification, comme milieux réactionnels ou encore pour la solubilisation de gaz ou de composés organiques volatils, sont abordées. Leurs atouts mais également leurs faiblesses sont discutés

«New Method for Volatile Organic Compounds Abatement»

International audienceno abstrac

Deep eutectic solvents incorporating cyclodextrins: promising candidates for the solubilisation of organic compounds

International audienc

«Deep Eutectic Solvents: A Novel Media for Cyclodextrin Inclusion Complexes Formation»

International audienceno abstrac

«Solvants eutectiques profonds : un nouveau milieu pour la formation de complexes d’inclusion à base de cyclodextrines»

National audienc

Patterns of human activity behavior: From data to information and clinical knowledge

Advances in wearable/mobile device technologies make possible long-Term recording of data in our everyday life contexts. Of particular interest is availability of inertial sensors allowing to monitor daily physical activity behavior, which is thought to include useful information on physiology, age/disease related functional capacity, and quality of life. The challenging task in this interdisciplinary research context is to translate the raw data into interpretable information and knowledge that can be further exploited to provide valid hypothesis, objective evaluation and diagnosis. The aim of this paper is to present a methodological framework that brings together monitoring technology, mathematical tools and modern clinical concepts of physiological complexity, with the aim to reveal and quantify aspects of age-/health-related physical behavior embedded in patterns of everyday life activity

Learning Laparoscopic Radical Hysterectomy: Are We Facing an Emerging Situation?

: Despite wide screening campaigns and early detection, cervical cancer remains the fourth most common cancer among women. Radical hysterectomy, whether by open, laparoscopic or by robotic-assisted techniques, is the mainstay treatment. However, for adequate surgical results and good oncological prognosis, a gynecological surgeon should be trained to perform those procedures. The learning curve of radical hysterectomy, especially by laparoscopy, is influenced by several factors. The LACC trial, the decrease in cervical cancer incidence and radical hysterectomy procedures have widely reduced the learning curve for surgeons. This article mainly discusses the learning curve of laparoscopic radical hysterectomy for cervical cancers, and how several factors are influencing it negatively, with the need to have medical authorities reset specific surgical training programs and allocate them to special oncological centers

Characterization of a novel variant in siblings with Asparagine Synthetase Deficiency.

Asparagine Synthetase Deficiency (ASD) is a recently described inborn error of metabolism caused by bi-allelic pathogenic variants in the asparagine synthetase (ASNS) gene. ASD typically presents congenitally with microcephaly and severe, often medically refractory, epilepsy. Development is generally severely affected at birth. Tone is abnormal with axial hypotonia and progressive appendicular spasticity. Hyperekplexia has been reported. Neuroimaging typically demonstrates gyral simplification, abnormal myelination, and progressive cerebral atrophy. The present report describes two siblings from consanguineous parents with a homozygous Arg49Gln variant associated with a milder form of ASD that is characterized by later onset of symptoms. Both siblings had a period of normal development before onset of seizures, and development regression. Primary fibroblast studies of the siblings and their parents document that homozygosity for Arg49Gln blocks cell growth in the absence of extracellular asparagine. Functional studies with these cells suggest no impact of the Arg49Gln variant on basal ASNS mRNA or protein levels, nor on regulation of the gene itself. Molecular modelling of the ASNS protein structure indicates that the Arg49Gln variant lies near the substrate binding site for glutamine. Collectively, the results suggest that the Arg49Gln variant affects the enzymatic function of ASNS. The clinical, cellular, and molecular observations from these siblings expand the known phenotypic spectrum of ASD

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+)/H(+) Exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, ages 4 to 19) with mutations in NHE6 were administered standardized research assessments and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants (SNVs), 2 indels and 1 CNV deletion. All mutations were protein-truncating or splicing mutations. We identified two recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, seven of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical and behavioral symptoms. All CS participants were non-verbal and had intellectual disability, epilepsy and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%) and MRI evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%) and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy and regression