Mutations in NSUN2 Cause Autosomal- Recessive Intellectual Disability

With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227∗] and c.1114C>T [p.Gln372∗], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs∗192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development

The Stubenberg meteorite—An LL6 chondrite fragmental breccia recovered soon after precise prediction of the strewn field

On March 6, 2016 at 21:36:51 UT, extended areas of Upper Austria, Bavaria (Germany) and the southwestern part of the Czech Republic were illuminated by a very bright bolide. This bolide was recorded by instruments in the Czech part of the European Fireball Network and it enabled complex and precise description of this event including prediction of the impact area. So far six meteorites totaling 1473 g have been found in the predicted area. The first pieces were recovered on March 12, 2016 on a field close to the village of Stubenberg (Bavaria). Stubenberg is a weakly shocked (S3) fragmental breccia consisting of abundant highly recrystallized rock fragments embedded in a clastic matrix. The texture, the large grain size of plagioclase, and the homogeneous compositions of olivine (Fa31.4) and pyroxene (Fs25.4) clearly indicate that Stubenberg is an LL6 chondrite breccia. This is consistent with the data on O, Ti, and Cr isotopes. Stubenberg does not contain solar wind-implanted noble gases. Data on the bulk chemistry, IR spectroscopy, cosmogenic nuclides, and organic components also indicate similarities to other metamorphosed LL chondrites. Noble gas studies reveal that the meteorite has a cosmic ray exposure (CRE) age of 36 ± 3 Ma and that most of the cosmogenic gases were produced in a meteoroid with a radius of at least 35 cm. This is larger than the size of the meteoroid which entered the Earth's atmosphere, which is constrained to <20 cm from short-lived radionuclide data. In combination, this might suggest a complex exposure history for Stubenberg.PostprintPeer reviewe

Understanding the crucial interactions between Cytochrome P450s and non-ribosomal peptide synthetases during glycopeptide antibiotic biosynthesis

The importance of Cytochrome P450-catalyzed modifications of natural products produced by non-ribosomal peptide synthetase machineries is most apparent during glycopeptide antibiotic biosynthesis: specifically, the formation of essential amino acid side chains crosslinks in the peptide backbone of these clinically relevant antibiotics. These cyclization reactions take place whilst the peptide substrate remains bound to the non-ribosomal peptide synthetase in a process mediated by a conserved domain of previously unknown function—the X-domain. This review addresses recent advances in understanding P450 recruitment to non-ribosomal peptide synthetase-bound substrates and highlights the importance of both carrier proteins and the X-domain in different P450-catalyzed reactions

PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study

In view of upcoming clinical trials, quantitative molecular markers accessible in peripheral blood are of critical importance as prognostic or pharmacodynamic markers in genetic neurodegenerative diseases such as Spinocerebellar Ataxia Type 3 (SCA3), in particular for signaling target engagement. In this pilot study, we focused on the quantification of ataxin-3, the protein altered in SCA3, in human peripheral blood mononuclear cells (PBMCs) acquired from preataxic and ataxic SCA3 mutation carriers as well as healthy controls, as a molecular marker directly related to SCA3 pathophysiology. We established two different highly sensitive TR-FRET-based immunoassays to measure the protein levels of either total full-length, non-expanded and expanded, ataxin-3 or specifically polyQ-expanded ataxin-3. In PBMCs, a clear discrimination between SCA3 mutation carrier and controls were seen measuring polyQ-expanded ataxin-3 protein level. Additionally, polyQ-expanded ataxin-3 protein levels correlated with disease progression and clinical severity as assessed by the Scale for the Assessment and Rating of Ataxia. Total full-length ataxin-3 protein levels were directly influenced by the expression levels of the polyQ-expanded ataxin-3 protein, but were not correlated with clinical parameters. Assessment of ataxin-3 levels in fibroblasts or induced pluripotent stem cells allowed to distinguish mutation carriers from controls, thus providing proof-of-principle validation of our PBMC findings across cell lines. Total full-length or polyQ-expanded ataxin-3 protein was not detectable by TR-FRET assays in other biofluids like plasma or cerebrospinal fluid, indicating the need for ultra-sensitive assays for these biofluids. Standardization studies revealed that tube systems, blood sampling, and PBMC preparation may influence ataxin-3 protein levels indicating a high demand for standardized protocols in biomarker studies. In conclusion, the polyQ-expanded ataxin-3 protein is a promising candidate as a molecular target engagement marker in SCA3 in future clinical trials, determinable even in-easily accessible-peripheral blood biomaterials. These results, however, require validation in a larger cohort and further standardization of modifying conditions