DLG4-related synaptopathy: a new rare brain disorder

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.Genetics of disease, diagnosis and treatmen

Effects of Genistein on beta-Catenin Signaling and Subcellular Distribution of Actin-Binding Proteins in Human Umbilical CD105-Positive Stromal Cells

This study was performed to define the roles of actin-binding proteins in the regulation of actin filament assembly associated with cellular signal transduction pathways in stromal cell proliferation. Genistein, a tyrosine protein kinase inhibitor, decreased the intracellular Ca(2+) and attenuated cell proliferation and DNA synthesis through the beta-catenin and cyclin D1 pathway in human umbilical CD105-positive cells. Immunoprecipitation studies using anti-beta-actin antibody revealed that several actin-binding proteins implicated in cells include formin-2 (FMN-2), caldesmon (CaD), tropomyosin (Tm), and profilin. Protein levels of these proteins in whole cell lysates were not significantly changed by genistein. Three Tm isoforms, Tm-1, Tm-2, and Tm-4, were found to be present in cells. Genistein caused a reduction in levels of mRNAs coding for Tm-1 and Tm-4, but had no significant effect on Tm-2 mRNA levels. Immunofluorescence confocal scanning microscopy indicated that changes in the subcellular distribution of Tm and CaD, in which the diffuse cytosolic staining was shifted to show colocalization with actin stress fibers. In contrast, genistein-induced accumulation of FMN-2 and profilin in the pen-nuclear area. Silencing of FMN-2 by small interfering RNA resulted in increases of intracellular Ca(2+) and rendered genistein resistance in decreasing intracellular Ca(2+) in cells. These results provide the novel findings that genistein acts by modulating the cellular distribution of actin-binding proteins in association with alterations of cellular signal transduction pathways in human stromal cell proliferation. J. Cell. Physiol. 223: 423-434, 2010. (C) 2010 Wiley-Liss, Inc

Control and detection of organosilane polarization on nanowire field-effect transistors

We demonstrated control and detection of UV-induced 3-aminopropyltriethoxysilane (APTES) polarization using silicon nanowire field-effect transistors made by top-down lithograph technology. The electric dipole moment in APTES films induced by UV-illumination was shown to produce negative effective charges. When individual dipoles were aligned with an externally applied electric field, the collective polarization can prevail over the UV-induced charges in the wires and give rise to an abnormal resistance enhancement in n-type wires. Real-time detection of hybridization of 15-mer poly-T/poly-A DNA molecules was performed, and the amount of hybridization-induced charges in the silicon wire was estimated. Based on these results, detection sensitivity of the wire sensors was discussed

Molecular imaging of cancer cells using plasmon-resonant-enhanced third-harmonic-generation in silver nanoparticles

We demonstrate molecule-specific third-harmonic-generation (THG) microscopy by using silver nanoparticles as THG contrast agents. Through matching surface plasmon wavelength to THG wavelength, strong contrast can be provided by silver nanoparticles under THG microscopy. By conjugating anti-her2 antibodies with silver nanoparticles, the expression of the Her2/neu oncogene in the cancer cell membranes is successfully imaged under THG modality for the first time