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

Cellular membrane potentials induced by alternating fields

Membrane potentials induced by external alternating fields are usually derived assuming that the membrane is insulating, that the cell has no surface conductance, and that the potentials are everywhere solutions of the Laplace equation. This traditional approach is reexamined taking into account membrane conductance, surface admittance, and space charge effects. We find that whenever the conductivity of the medium outside the cell is low, large corrections are needed. Thus, in most of the cases where cells are manipulated by external fields (pore formation, cell fusion, cell rotation, dielectrophoresis) the field applied to the cell membrane is significantly reduced, sometimes practically abolished. This could have a strong bearing on present theories of pore formation, and of the influence of weak electric fields on membranes

Electrical Properties of the Membranes of the Pleuropneumonia-Like Organism A 5969

The electrical properties of the pleuropneumonia-like organism A 5969 have been determined over the frequency range from 0.5 to 250 Mcps. The frequency dependence of the dielectric constant and conductivity of PPLO suspensions is completely consistent with the existence of a membrane. The PPLO has an internal conductance which in part reflects its ionic equilibrium with normal nutrient and macromolecular constituents. But it is fairly independent from variation in external ionic strength

On the Possibility of Nonthermal Biological Effects of Pulsed Electromagnetic Radiation

Two mechanisms for the interaction of alternating electrical fields with biological tissue are the development of heat, via i(2)R losses, and field-induced force effects, via differences in passive electrical properties. It has been shown that for continuous wave (CW) fields in media of physiologic electrical conductivity, the development of heat (>1°C) always precedes the possible appearance of a field-induced force effect. Using pearl-chain formation as a model effect and experimentally demonstrating that its time constant varies inversely as the square of the electrical field strength, we show that a pulsed field has no greater ability than a CW field of equal rms field strength to produce a field-induced force effect. Thus, the statement above for CW fields can be broadened to include pulsed fields of any description. By relating incident power density to electric field strength in tissue, we show that the American National Standards Institute's radiation protection guide obviates the production of genetic effects in man, if they exist, via field-induced force effects