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Δευτέρα 30 Απριλίου 2018
ResQPOD ITD Overview
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ResQPOD ITD Overview
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ELMOD3 , a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss
Abstract
Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identified. The goal of this study was to determine the causative gene in a five-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two affected individuals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional effect of the identified variant, in-vitro studies were performed. novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL. The variant was validated by Sanger sequencing and found to co-segregate with the phenotype within the pedigree and was absent in 500 ethnically matched unrelated normal hearing control subjects. To our knowledge, this is the first report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immunofluorescence staining demonstrated that p.His171Arg resulted in abnormal expression levels of ELMOD3 and abnormal subcellular localization. Furthermore, the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family of GTPase-activating proteins, was identified for the first time as responsible for ADNSHL.
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Prions, prionoids and protein misfolding disorders
Prions, prionoids and protein misfolding disorders
Prions, prionoids and protein misfolding disorders, Published online: 30 April 2018; doi:10.1038/s41576-018-0011-4
Parallels are increasingly being drawn between prion diseases and other aggregate-mediated neurodegenerative disorders. While prion diseases are a distinct subclass of protein misfolding disorders (PMDs), a better understanding of shared mechanisms is likely to benefit treatment of all PMDs.
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Portable X-ray fluorescence system to measure Th and U concentrations
Source:Journal of Environmental Radioactivity, Volume 189
Author(s): Marcilei A. Guazzelli da Silveira, Bruno Ribeiro Pereira, Nilberto H. Medina, Marcia A. Rizzutto
This study reports the results obtained in the analysis of waste material samples generated by the industries of phosphate fertilizers, in particular, the use of specific filters in a portable X-ray fluorescence system, a simple equipment allowing the characterization, identification and quantification of low concentrations of Th and U (ppm). The industrial byproduct is classified as a Technologically-Enhanced, Naturally-Occurring Radioactive Material - TENORM, and therefore requires monitoring for its radio-toxic activity due to the presence of radioactive thorium and uranium families. From the results obtained, it is concluded that this technique is able to determine the contents of these elements to concentrations of tens of ppm in measurements of about 300 s, and a small sample amount (∼0.1 g).
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A zebrafish model of foxe3 deficiency demonstrates lens and eye defects with dysregulation of key genes involved in cataract formation in humans
Abstract
The Forkhead box E3 (FOXE3) gene encodes a transcription factor with a forkhead/winged helix domain that is critical for development of the lens and anterior segment of the eye. Monoallelic and biallelic deleterious sequence variants in FOXE3 cause aphakia, cataracts, sclerocornea and microphthalmia in humans. We used clustered regularly interspaced short palindromic repeats/Cas9 injections to target the foxe3 transcript in zebrafish in order to create an experimental model of loss of function for this gene. Larvae that were homozygous for an indel variant, c.296_300delTGCAG, predicting p.(Val99Alafs*2), demonstrated severe eye defects, including small or absent lenses and microphthalmia. The lenses of the homozygous foxe3 indel mutants showed more intense staining with zl-1 antibody compared to control lenses, consistent with increased lens fiber cell differentiation. Whole genome transcriptome analysis (RNA-Seq) on RNA isolated from wildtype larvae and larvae with eye defects that were putative homozygotes for the foxe3 indel variant found significant dysregulation of genes expressed in the lens and eye whose orthologues are associated with cataracts in human patients, including cryba2a, cryba1l1, mipa and hsf4. Comparative analysis of this RNA-seq data with iSyTE data identified several lens-enriched genes to be down-regulated in foxe3 indel mutants. We also noted upregulation of lgsn and crygmxl2 and downregulation of fmodb and cx43.4, genes that are expressed in the zebrafish lens, but that are not yet associated with an eye phenotype in humans. These findings demonstrate that this new zebrafish foxe3 mutant model is highly relevant to the study of the gene regulatory networks conserved in vertebrate lens and eye development.
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