Extracellular proteases and their inhibitors ingenetic diseases of the central nervous system

Cumulative evidence has shown that a delicate balance between serine proteases and their inhibitors is crucial for normal functioning of several biological pathways. The importance of proteases and their inhibitors is well documented in several human diseases. Among them, the best documented are hemophilia B, a genetic deficiency of the serine protease coagulation factor IX and serpinophathies. Alpha-1-antitrypsin deficiency (MIM 107400), is associated with early-onset emphysema and liver disease, while hereditary angioedema (HANE; MIM 106100) is caused by mutations in the C1 inhibitor, a serpin involved in the regulation of the complement cascade. Recently, two human genetic diseases of the central nervous system have been related to mutations in components of extracellular proteolytic systems. Here, we review the recent advances in this fiel

Universal Code Equivalent of a Yeast Mitochondrial lntron Reading Frame Is Expressed into E. coli as a Specific Double Strand Endonuclease

International audienceThe intron of the mitochondrial21S rRNA gene of Sac-charomyces cerevisiae (rl intron) possesses a 235 codon long internal open reading frame (rl ORF) whose translation product determines the duplicative transposition of that intron during crosses between intron-plus strains (omega+) and intron-minus ones (omega-). Using site-directed mutagenesis, we have constructed a universal code equivalent of the rl ORF that, under appropriate promoter control, allows the overexpression in E. coli of a protein identical to the mitochondrial intron encoded "transposase". This protein exhibits a double strand endonuclease activity specific for the omega-site. This finding demonstrates , for the first time, the enzymatic activity of an intron encoded protein whose function is to promote the spreading of that intron by generating double strand breaks at a specific sequence within a gene

Ультрадисперсные порошки на основе железа как катализаторы синтеза жидких углеводородов из СО и Н[2]

International audienceTo date, uniparental disomy (UPD) with phenotypic relevance is described for different chromosomes and it is likely that additional as yet unidentified UPD phenotypes exist. Due to technical difficulties and limitations of time and resources, molecular analyses for UPD using microsatellite markers are only performed in cases with specific phenotypic features. In this study, we carried out a whole genome UPD screening based on a microarray genotyping technique. Six patients with the diagnosis of both complete or segmental UPD including Prader-Willi syndrome (PWS; matUPD15), Angelman syndrome (AS; patUPD15), Silver-Russell syndrome (SRS; matUPD7), Beckwith-Wiedemann syndrome (BWS; patUPD11p), pseudohypoparathyroidism (PHP; patUPD20q) and a rare chromosomal rearrangement (patUPD2p, matUPD2q), were genotyped using the GeneChip Human Mapping 10K Array. Our results demonstrate the presence of UPD in the patients with high efficiency and reveal clues about the mechanisms of UPD formation. We thus conclude that array based SNP genotyping is a fast, cost-effective, and reliable approach for whole genome UPD screening

Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population

International audienceAbstractBackgroundCerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Patients with these signs also typically present with non-specific neuroimaging results that can help prioritize further investigation but don’t suggest a specific molecular diagnosis.MethodsTo genetically explore a cohort of 18 Egyptian families with undiagnosed cerebellar atrophy identified on MRI, we sequenced probands and some non-affected family members via high-coverage whole exome sequencing (WES; >97 % of the exome covered at least by 30x). Patients were mostly from consanguineous families, either sporadic or multiplex. We analyzed WES data and filtered variants according to dominant and recessive inheritance models.ResultsWe successfully identified disease-causing mutations in half of the families screened (9/18). These mutations are located in seven different genes, PLA2G6 being the gene most frequently mutated (n = 3). We also identified a recurrent de novo mutation in the KIF1A gene and a molybdenum cofactor deficiency caused by the loss of the start codon in the MOCS2A open-reading frame in a mildly affected subject.ConclusionsThis study illustrates the necessity of screening for dominant mutations in WES data from consanguineous families. Our identification of a patient with a mild and improving phenotype carrying a previously characterized severe loss of function mutation also broadens the clinical spectrum associated with molybdenum cofactor deficiency

Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia

Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition

Analyse fonctionnelle d'une proteine codee par un intron du groupe un de la mitochondrie de levure : la transposase omega

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Identification et analyse fonctionnelle de gènes de retards mentaux autosomiques récessifs (vers l'identification de nouveaux mécanismes physiopathologiques)

Le retard mental (RM) se caractérise par un quotient intellectuel inférieur à 70 en utilisant la stratégie de cartographie par homozygote, nous avons étudié cinq familles consanguines multiplex et identifié le gène en cause pour deux d'entre elles. Le premier (PRSS12), impliqué dans un RM sévère isolé, code la neurotrypsine, protéase à sérine fortement exprimée dans le cerveau. Le second gène (SLC25A22), responsable d'un RM sévère associé à une épilepsie myoclonique précoce, code une protéine de la membrane interne mitochondriale impliquée dans le transport du glutamate. Nous avons ensuite établi leur patron d'expression spatio-temporelle au cours du développement embryonnaire et foetal humain. En parallèle nous avons construit et analysé la drosophile "Knock-Down" pour "Tequila", l'homologue de PRSS12. Enfin, nous avons analysé les conséquences de la mutationPARIS5-BU-Necker : Fermée (751152101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Tequila, a Neurotrypsin Ortholog, Regulates Long-Term Memory Formation in Drosophila

International audienc