Severe congenital microcephaly with AP4M1 mutation, a case report

Background: Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset. Case presentation: We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly. Conclusions: Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly

Evolution monitoring of a solution-mining cavern in salt : identifying and analysing early-warning signals prior to collapse

International audienceRisk management of underground cavities requires a good working knowledge of accidental phenomena like subsidence or large-scale collapse. This was the context when the opportunity was taken to instrument a large size in use saline cavern, so as to test various auscultation techniques available under controlled conditions. A microseismic monitoring network coupled to a surface measurement system was installed to improve our knowledge of the mechanisms that initiate and govern the evolution of the cavern up to its collapse. After a stationary period combined with partial depressurization tests conducted in 2005 and 2007, the cavern appears to have entered into its final evolution phase, and this probably since early 2008. This results in continuous and highly sustained microseismic activity as well as the occurrence of a number of microseismic episodes localized around the cavern roof. The localization of the microseismic events, for some of these episodes, is closely correlated to the quasi-dynamic brine pressure variations and to the evolutions of the roof depth measured at observation boreholes. The microseismic activity turns out to be more precise when it comes to the evolution affecting the mine cavern than the movement measurements taken on the surface or sub-surface

Homologous Transcription Factors DUX4 and DUX4c Associate with Cytoplasmic Proteins during Muscle Differentiation

Hundreds of double homeobox (DUX) genes map within 3.3-kb repeated elements dispersed in the human genome and encode DNA-binding proteins. Among these, we identified DUX4, a potent transcription factor that causes facioscapulohumeral muscular dystrophy (FSHD). In the present study, we performed yeast two-hybrid screens and protein co-purifications with HaloTag-DUX fusions or GST-DUX4 pull-down to identify protein partners of DUX4, DUX4c (which is identical to DUX4 except for the end of the carboxyl terminal domain) and DUX1 (which is limited to the double homeodomain). Unexpectedly, we identified and validated (by co-immunoprecipitation, GST pull-down, co-immunofluorescence and in situ Proximal Ligation Assay) the interaction of DUX4, DUX4c and DUX1 with type III intermediate filament protein desmin in the cytoplasm and at the nuclear periphery. Desmin filaments link adjacent sarcomere at the Z-discs, connect them to sarcolemma proteins and interact with mitochondria. These intermediate filament also contact the nuclear lamina and contribute to positioning of the nuclei. Another Z-disc protein, LMCD1 that contains a LIM domain was also validated as a DUX4 partner. The functionality of DUX4 or DUX4c interactions with cytoplasmic proteins is underscored by the cytoplasmic detection of DUX4/DUX4c upon myoblast fusion. In addition, we identified and validated (by co-immunoprecipitation, co-immunofluorescence and in situ Proximal Ligation Assay) as DUX4/4c partners several RNA-binding proteins such as C1QBP, SRSF9, RBM3, FUS/TLS and SFPQ that are involved in mRNA splicing and translation. FUS and SFPQ are nuclear proteins, however their cytoplasmic translocation was reported in neuronal cells where they associated with ribonucleoparticles (RNPs). Several other validated or identified DUX4/DUX4c partners are also contained in mRNP granules, and the co-localizations with cytoplasmic DAPI-positive spots is in keeping with such an association. Large muscle RNPs were recently shown to exit the nucleus via a novel mechanism of nuclear envelope budding. Following DUX4 or DUX4c overexpression in muscle cell cultures, we observed their association with similar nuclear buds. In conclusion, our study demonstrated unexpected interactions of DUX4/4c with cytoplasmic proteins playing major roles during muscle differentiation. Further investigations are on-going to evaluate whether these interactions play roles during muscle regeneration as previously suggested for DUX4c

Congenital hydrocephalus : new Mendelian mutations and evidence for oligogenic inheritance

Peer reviewe

Oncogènes et contrôle cellulaire

info:eu-repo/semantics/nonPublishe

Etude de la régulation d'expression des familles de protooncogènes jun et myc en réponse à différentes stimulations mitogéniques du thyrocyte.

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Oncogènes et croissance cellulaire

info:eu-repo/semantics/nonPublishe

Oncogènes, gènes suppresseurs et contrôle du cycle cellulaire

info:eu-repo/semantics/nonPublishe

Pitfalls in the use of transfected overexpression systems to study membrane proteins function: the case of TSH receptor and PRA1.

Thyrotropin (TSH) stimulates thyroid cell differentiation and proliferation by binding to its G-protein coupled receptor (GPCR) receptor, the thyrotropin receptor (TSHR). To understand some differences in transduction between human and dog cells a search for partners proteins was performed by a two-hybrid screen with the dog C-terminal tail of the receptor as bait. Prenylated Rab acceptor 1 (PRA1) was identified by this way. Pursuing with the characterization of the biochemical interaction, we performed co-transfection experiments in COS-7 cells and we observed, by measurement of the intracellular cAMP produced and by FACS experiments, that the co-expression of two membrane proteins (PRA1, NIS, LH/CGR with TSHR) alters their expression. This effect seems to be restricted to co-expression of two-membrane proteins because the expression does not decrease when the membrane protein is co-expressed with a cytosolic protein (Rab9, Cyclin D3). This pitfall should be considered in such expression experiments.Evaluation StudiesJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe