Objective: Galloway-Mowat syndrome (GAMOS) is a neural and renal disorder, characterized by microcephaly, brain anomalies, and early onset nephrotic syndrome. Biallelic mutations in WDR73 and the 4 subunit genes of the KEOPS complex are reported to cause GAMOS. Furthermore, an identical homozygous NUP107 (nucleoporin 107kDa) mutation was identified in 4 GAMOS-like families, although biallelic NUP107 mutations were originally identified in steroidresistant nephrotic syndrome. NUP107 and NUP133 (nucleoporin 133kDa) are interacting subunits of the nuclear pore complex in the nuclear envelope during interphase, and these proteins are also involved in centrosome positioning and spindle assembly during mitosis. Methods: Linkage analysis and whole exome sequencing were performed in a previously reported GAMOS family with brain atrophy and steroid-resistant nephrotic syndrome. Results: We identified a homozygous NUP133 mutation, c.3335-11T>A, which results in the insertion of 9bp of intronic sequence between exons 25 and 26 in the mutant transcript. NUP133 and NUP107 interaction was impaired by the NUP133 mutation based on an immunoprecipitation assay. Importantly, focal cortical dysplasia type IIa was recognized in the brain of an autopsied patient and focal segmental glomerulosclerosis was confirmed in the kidneys of the 3 examined patients. A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal cells, underdeveloped glomeruli, and fusion of the foot processes of the podocytes, which mimicked human GAMOS features. nup133 morphants could be rescued by human wild-type NUP133 mRNA but not by mutant mRNA. Interpretation: These data indicate that the biallelic NUP133 loss-of-function mutation causes GAMOS.

Intracellular vesicular transport is important for photoreceptor function and maintenance. However, the mechanism underlying photoreceptor degeneration in response to vesicular transport defects is unknown. Here, we report that photoreceptors undergo apoptosis in a zebrafish β-soluble N-ethylmaleimide-sensitive factor attachment protein (β-SNAP) mutant. β-SNAP cooperates with N-ethylmaleimide-sensitive factor to recycle the SNAP receptor (SNARE), a key component of the membrane fusion machinery, by disassembling the cis-SNARE complex generated in the vesicular fusion process. We found that photoreceptor apoptosis in the β-SNAP mutant was dependent on the BH3-only protein BNip1. BNip1 functions as a component of the syntaxin-18 SNARE complex and regulates retrograde transport from the Golgi to the endoplasmic reticulum. Failure to disassemble the syntaxin-18 cis-SNARE complex caused BNip1-dependent apoptosis. These data suggest that the syntaxin-18 cis-SNARE complex functions as an alarm factor that monitors vesicular fusion competence and that BNip1 transforms vesicular fusion defects into photoreceptor apoptosis.

Genetic mutations in aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) cause photoreceptor degeneration associated with Leber congenital amaurosis 4 (LCA4) in human patients. Here we report retinal phenotypes of a zebrafish aipl1 mutant, gold rush (gosh). In zebrafish, there are two aipl1 genes, aipl1a and aipl1b, which are expressed mainly in rods and cones, respectively. The gosh mutant gene encodes cone-specific aipl1, aipl1b. Cone photoreceptors undergo progressive degeneration in the gosh mutant, indicating that aipl1b is required for cone survival. Furthermore, the cone-specific subunit of cGMP phosphodiesterase 6 (Pde6c) is markedly decreased in the gosh mutant, and the gosh mutation genetically interacts with zebrafish pde6c mutation eclipse (els). These data suggest that Aipl1 is required for Pde6c stability and function. In addition to Pde6c, we found that zebrafish cone-specific guanylate cyclase, zGc3, is also decreased in the gosh and els mutants. Furthermore, zGc3 knockdown embryos showed a marked reduction in Pde6c. These observations illustrate the interdependence of cGMP metabolism regulators between Aipl1, Pde6c, and Gc3 in photoreceptors.

Abstract:The ATP1 gene (YBL099w) encoding the F 1 F 0 -ATPase complex subunit of Saccharomyces cerevisiae is present on the left arm close to the telomere of chromosome II, and only one copy was reported by the Genome Project. Recently, we reported that three ATP1s designated ATP1a, ATP1b and ATP1c are located on chromosome II, with different distances between ATP1a and ATP1b, and ATP1b and ATP1c as identified previously. To elucidate the ATP1 repetition and their junction sites, we report here the complete nucleotide sequence of this region (approximately 35 kb) on the left arm of chromosome II in Saccharomyces cerevisiae using the prime clones 70113 and 70804 from ATCC, and genomic DNAs from various yeast strains S288C, DC5, W303-1A and those of the gene copy-specific ATP1-disruptants. The nucleotide sequences of the three ATP1s were identical, and they were repeated along with differing amounts of neighboring DNA sequences.The nucleotide sequence of the ATP1 repeat region has been deposited to DDBJ (AB304259, 20070511181828.08607).

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Background: Experiments with small electrochemical apparatus were previously carried out for detecting low-energy neutrinos under irradiation of reactor neutrinos and under natural neutrino environment. The experimental result indicated that the output current of reactorneutrino irradiated detector was appreciably larger than that of natural environmental one. Usual interaction cross-sections of neutrinos are quite small, so that they do not explain the experimental result at all. Materials and Methods: To understand the experimental data, we propose that some biological products may generate AV-type scalar field B 0 , leading to a large interaction cross-section. The output current generation is ascribed to an electrochemical process that may be assisted by weak interaction phenomena. Dissolved oxygen concentrations in the detector solution were measured in this study, for the purpose of understanding the mechanism of the detector output current generation. Results and Discussion: It was found that the time evolution of experimental output current was mostly reproduced in simulation calculation on the basis of the measured dissolved oxygen concentration. Conclusion: We mostly explained the variation of experimental data by using the electrochemical half-cell analysis model based on the DO concentration that is consistent to the experiment.