scholarly journals The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

2019 ◽  
Author(s):  
Robert G. Mealer ◽  
Bruce G. Jenkins ◽  
Chia-Yen Chen ◽  
Mark J. Daly ◽  
Tian Ge ◽  
...  
Keyword(s):  
Brain Mri ◽  
Trace Element Analysis ◽  
Missense Variant ◽  
Common Variant ◽  
Loss Of Function ◽  
Element Analysis ◽  
Glycome Profiling ◽  
Depth Analysis ◽  
Mri Scans ◽  
The Common

AbstractA common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease.SummaryA common variant in the manganese transporter SLC39A8 is associated with numerous phenotypes including schizophrenia. Mealer et. al. presents an in-depth analysis of brain MRI and plasma glycomics in human carriers of the common variant, identifying several manganese-related changes with potential for diagnostic and therapeutic biomarker development.

scholarly journals Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

2020 ◽  
Vol 29 (13) ◽  
pp. 2218-2239 ◽  
Author(s):  
Anne Slavotinek ◽  
Doriana Misceo ◽  
Stephanie Htun ◽  
Linda Mathisen ◽  
Eirik Frengen ◽  
...  
Keyword(s):  
Short Stature ◽  
Mammalian Cells ◽  
Developmental Delays ◽  
Brain Mri ◽  
Missense Variant ◽  
Cerebellar Hypoplasia ◽  
Loss Of Function ◽  
Feeding Difficulties ◽  
In Trans ◽  
Rna Exosome

Abstract The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5–6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

scholarly journals Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders

Brain ◽  
2020 ◽  
Author(s):  
Fanny Mochel ◽  
Agnès Rastetter ◽  
Berten Ceulemans ◽  
Konrad Platzer ◽  
Sandra Yang ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Movement Disorders ◽  
De Novo ◽  
Brain Mri ◽  
Missense Variant ◽  
Loss Of Function ◽  
Patch Clamp Technique ◽  
Abnormal Gait ◽  
Frameshift Deletion ◽  
Uncertain Significance

Abstract KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

scholarly journals Detection and Analytical Capabilities for Trace Level of Carbon in High-Purity Metals by Laser-Induced Breakdown Spectroscopy with a Frequency Quintupled 213 nm Nd:YAG Laser

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Masaki Ohata ◽  
Toshiki Nakae
Keyword(s):  
High Purity ◽  
Nd:Yag Laser ◽  
Inductively Coupled Plasma ◽  
Trace Element Analysis ◽  
Laser Induced Breakdown Spectroscopy ◽  
Trace Level ◽  
Element Analysis ◽  
Breakdown Spectroscopy ◽  
Depth Analysis ◽  
Laser Induced Breakdown

The laser-induced breakdown spectroscopy (LIBS) with a frequency quintupled 213 nm Nd:YAG laser was examined to the analysis of trace level of carbon (C) in high-purity metals and its detection and analytical capabilities were evaluated. Though C signal in a wavelength of 247.9 nm, which showed the highest sensitivity of C, could be obtained from Cd, Ti, and Zn ca. 7000 mg kg−1 C in Fe could not be detected due to the interferences from a lot of Fe spectra. Alternative C signal in a wavelength of 193.1 nm could not be also detected from Fe due to the insufficient laser output energy of the frequency quintupled 213 nm Nd:YAG laser. The depth analysis of C by LIBS was also demonstrated and the C in Cd and Zn was found to be contaminated in only surface area whereas the C in Ti was distributed in bulk. From these results, the frequency quintupled 213 nm Nd:YAG laser, which was adopted widely as a commercial laser ablation (LA) system coupled with inductively coupled plasma mass spectrometry (ICPMS) for trace element analysis in solid materials, could be used for C analysis to achieve simultaneous measurements for both C and trace elements in metals by LIBS and LA-ICPMS, respectively.

scholarly journals Clinical Chemistry: A Challenge for High-Purity Standards and Reagents

1971 ◽  
Vol 17 (9) ◽  
pp. 833-840 ◽  
Author(s):  
M Zief ◽  
F W Michelotti
Keyword(s):  
Clinical Laboratory ◽  
Clinical Chemistry ◽  
Primary Standard ◽  
Trace Element Analysis ◽  
Chemistry Laboratory ◽  
Element Analysis ◽  
Clinical Chemistry Laboratory ◽  
The Common ◽  
Precision And Accuracy ◽  
Dynamic Interplay

Abstract The dynamic interplay between preparation, handling, containment, and analysis of ultrapure chemical standards and reagents for the clinical chemistry laboratory is described. Inorganic as well as organic standards are reviewed. The contamination problems associated with water, acids, and solvents in trace-element analysis are defined and resolved. In addition, less well-known sources of error in trace analysis are reviewed, as are the common contaminants in the clinical laboratory. It does little good to use a 99.99% primary standard with water of unknown quality in a heavily contaminated laboratory. Fortunately, recognition, definition, and solution of this problem is possible and should introduce new levels of precision and accuracy in the clinical chemistry laboratory.

scholarly journals Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

2020 ◽  
Author(s):  
Anne Slavotinek ◽  
Doriana Misceo ◽  
Stephanie Htun ◽  
Linda Mathisen ◽  
Eirik Frengen ◽  
...  
Keyword(s):  
Short Stature ◽  
Mammalian Cells ◽  
Developmental Delays ◽  
Brain Mri ◽  
Failure To Thrive ◽  
Missense Variant ◽  
Cerebellar Hypoplasia ◽  
Loss Of Function ◽  
Feeding Difficulties ◽  
Rna Exosome

AbstractThe RNA exosome is an essential ribonuclease complex involved in the processing and degradation of both coding and noncoding RNAs. We present three patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The common clinical features of these patients comprise failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His, and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess the functional consequences of pathogenic variants in EXOSC5. Loss of function for the zebrafish ortholog results in shortened and curved tails and bodies, reduced eye and head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants show defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. Overall, these findings expand the number of genes encoding RNA exosome components that have been implicated in human disease, while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

An improved interference correction for trace element analysis

1992 ◽  
Vol 50 (2) ◽  
pp. 1646-1647
Author(s):  
John J. Donovan ◽  
Donald A. Snyder ◽  
Mark L. Rivers
Keyword(s):  
Trace Element Analysis ◽  
Accurate Estimate ◽  
Simple Expression ◽  
Standard Reference Materials ◽  
Characteristic Line ◽  
Analytical Line ◽  
Element Analysis ◽  
Electron Probe Analysis ◽  
Calculated Concentration ◽  
X Ray

We present a simple expression for the quantitative treatment of interference corrections in x-ray analysis. WDS electron probe analysis of standard reference materials illustrate the success of the technique.For the analytical line of wavelength λ of any element A which lies near or on any characteristic line of another element B, the observed x-ray counts at We use to denote x-ray counts excited by element i in matrix j (u=unknown; s=analytical standard; ŝ=interference standard) at the wavelength of the analytical line of A, λA (Fig. 1). Quantitative analysis of A requires an accurate estimate of These counts can be estimated from the ZAF calculated concentration of B in the unknown C,Bu measured counts at λA in an interference standard of known concentration of B (and containing no A), and ZAF correction parameters for the matrices of both the unknown and the interference standard at It can be shown that:

Reconstructing sea turtle ontogenetic habitat shifts through trace element analysis of bone tissue

2019 ◽  
Vol 608 ◽  
pp. 247-262 ◽  
Author(s):  
MD Ramirez ◽  
JA Miller ◽  
E Parks ◽  
L Avens ◽  
LR Goshe ◽  
...  
Keyword(s):  
Trace Element ◽  
Bone Tissue ◽  
Trace Element Analysis ◽  
Sea Turtle ◽  
Element Analysis ◽  
Ontogenetic Habitat Shifts

Method of Detecting Trace Metal Contamination in Thick-Film SOI Device

2005 ◽  
Author(s):  
Yasunori Goto ◽  
Hiroomi Eguchi ◽  
Masaru Iida
Keyword(s):  
Trace Metal ◽  
Thick Film ◽  
Metal Contamination ◽  
Semiconductor Device ◽  
Trace Element Analysis ◽  
Silicon On Insulator ◽  
Element Analysis ◽  
Trace Metal Contamination ◽  
Trace Metal Elements ◽  
Output Characteristics

Abstract In the automotive IC using thick-film silicon on insulator (SOI) semiconductor device, if the gettering capability of a SOI wafer is inadequate, electrical characteristics degradation by metal contamination arises and the yield falls. At this time, an automotive IC was made experimentally for evaluation of the gettering capability as one of the purposes. In this IC, one of the output characteristics varied from the standard, therefore failure analysis was performed, which found trace metal elements as one of the causes. By making full use of 3D perspective, it is possible to fabricate a site-specific sample into 0.1 micrometre in thickness without missing a failure point that has very minute quantities of contaminant in a semiconductor device. Using energy dispersive X-ray, it is possible to detect trace metal contamination at levels 1E12 atoms per sq cm. that are conventionally detected only by trace element analysis.

Trace Element Analysis of Fusel Oil by Microwave-Induced Plasma Optical Emission Spectrometry

2017 ◽  
Vol 13 (6) ◽  
Author(s):  
Daniel Araujo Goncalves ◽  
Tina McSweeney ◽  
Mirian Cristina dos Santos ◽  
Marco A. Utrera Martines ◽  
Luiz Francisco Malmonge ◽  
...  
Keyword(s):  
Trace Element ◽  
Trace Element Analysis ◽  
Optical Emission ◽  
Optical Emission Spectrometry ◽  
Emission Spectrometry ◽  
Element Analysis ◽  
Fusel Oil ◽  
Microwave Induced Plasma ◽  
Plasma Optical Emission Spectrometry
Sign in / Sign up

Export Citation Format

Share Document