Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with Meesmann corneal dystrophy.

PurposeTo report potentially pathogenic mutations in the keratin 3 (KRT3) and keratin 12 (KRT12) genes in two individuals with clinically diagnosed Meesmann corneal dystrophy (MECD).MethodsSlit-lamp examination was performed on the probands and available family members to identify characteristic features of MECD. After informed consent was obtained, saliva samples were obtained as a source of genomic DNA, and screening of KRT3 and KRT12 was performed. Potentially pathogenic variants were screened for in 200 control chromosomes. PolyPhen-2, SIFT, and PANTHER were used to predict the functional impact of identified variants. Short tandem repeat genotyping was performed to confirm paternity.ResultsSlit-lamp examination of the first proband demonstrated bilateral, diffusely distributed, clear epithelial microcysts, consistent with MECD. Screening of KRT3 revealed a heterozygous missense variant in exon 1, c.250C>T (p.(Arg84Trp)), which has a minor allele frequency of 0.0076 and was not identified in 200 control chromosomes. In silico analysis with PolyPhen-2 and PANTHER predicted the variant to be damaging to protein function; however, SIFT analysis predicted tolerance of the variant. The second proband demonstrated bilateral, diffusely distributed epithelial opacities that appeared gray-white on direct illumination and translucent on retroillumination. Neither parent demonstrated corneal opacities. Screening of KRT12 revealed a novel heterozygous insertion/deletion variant in exon 6, c.1288_1293delinsAGCCCT (p.(Arg430_Arg431delinsSerPro)). This variant was not present in either of the proband's parents or in 200 control chromosomes and was predicted to be damaging by PolyPhen-2, PANTHER, and SIFT. Haplotype analysis confirmed paternity of the second proband, indicating that the variant arose de novo.ConclusionsWe present a novel KRT12 mutation, representing the first de novo mutation and the first indel in KRT12 associated with MECD. In addition, we report a variant of uncertain significance in KRT3 in an individual with MECD. Although the potential pathogenicity of this variant is unknown, it is the first variant affecting the head domain of K3 to be reported in an individual with MECD and suggests that disease-causing variants associated with MECD may not be restricted to primary sequence alterations of either the helix-initiation or helix-termination motifs of K3 and K12

Spatial disparities in the reported incidence and survival of myeloproliferative neoplasms in Australia

Acknowledgments:The authors wish to thank the MPN Alliance Australia for motivating this study and financial support. We would also like to thank the reviewers for their helpful comments. Funding: was provided by the MPN Alliance Australia. The MPN Alliance Australia did not play any role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.Peer reviewedPostprintPostprintPostprin

A new mouse model of elastin haploinsufficiency highlights the importance of elastin to vascular development and blood pressure regulation

Supravalvular aortic stenosis (SVAS) is an autosomal dominant disease resulting from elastin (ELN) haploinsufficiency. Individuals with SVAS typically develop a thickened arterial media with an increased number of elastic lamellae and smooth muscle cell (SMC) layers and stenosis superior to the aortic valve. A mouse model of SVAS (El

O5‐08‐01: Trends In Racial And Ethnic Differences In Dementia Prevalence Rates And Disease Awareness

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153266/1/alzjjalz2019064876.pd

Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin

Actively transcribed regions of the genome are vulnerable to genomic instability. Recently, it was discovered that transcription is repressed in response to neighboring DNA double-strand breaks (DSBs). It is not known whether a failure to silence transcription flanking DSBs has any impact on DNA repair efficiency or whether chromatin remodelers contribute to the process. Here, we show that the PBAF remodeling complex is important for DSB-induced transcriptional silencing and promotes repair of a subset of DNA DSBs at early time points, which can be rescued by inhibiting transcription globally. An ATM phosphorylation site on BAF180, a PBAF subunit, is required for both processes. Furthermore, we find that subunits of the PRC1 and PRC2 polycomb group complexes are similarly required for DSB-induced silencing and promoting repair. Cancer-associated BAF180 mutants are unable to restore these functions, suggesting PBAF's role in repressing transcription near DSBs may contribute to its tumor suppressor activity

Racial and Ethnic Differences in Knowledge About One’s Dementia Status

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156478/1/jgs16442.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156478/3/jgs16442_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156478/2/jgs16442-sup-0001-supinfo.pd

Extracting Statistical Graph Features for Accurate and Efficient Time Series Classification

This paper presents a multiscale visibility graph representation for time series as well as feature extraction methods for time series classification (TSC). Unlike traditional TSC approaches that seek to find global similarities in time series databases (eg., Nearest Neighbor with Dynamic Time Warping distance) or methods specializing in locating local patterns/subsequences (eg., shapelets), we extract solely statistical features from graphs that are generated from time series. Specifically, we augment time series by means of their multiscale approximations, which are further transformed into a set of visibility graphs. After extracting probability distributions of small motifs, density, assortativity, etc., these features are used for building highly accurate classification models using generic classifiers (eg., Support Vector Machine and eXtreme Gradient Boosting). Thanks to the way how we transform time series into graphs and extract features from them, we are able to capture both global and local features from time series. Based on extensive experiments on a large number of open datasets and comparison with five state-of-the-art TSC algorithms, our approach is shown to be both accurate and efficient: it is more accurate than Learning Shapelets and at the same time faster than Fast Shapelets

Gene duplication and paleopolyploidy in soybean and the implications for whole genome sequencing

<p>Abstract</p> <p>Background</p> <p>Soybean, <it>Glycine max </it>(L.) Merr., is a well documented paleopolyploid. What remains relatively under characterized is the level of sequence identity in retained homeologous regions of the genome. Recently, the Department of Energy Joint Genome Institute and United States Department of Agriculture jointly announced the sequencing of the soybean genome. One of the initial concerns is to what extent sequence identity in homeologous regions would have on whole genome shotgun sequence assembly.</p> <p>Results</p> <p>Seventeen BACs representing ~2.03 Mb were sequenced as representative potential homeologous regions from the soybean genome. Genetic mapping of each BAC shows that 11 of the 20 chromosomes are represented. Sequence comparisons between homeologous BACs shows that the soybean genome is a mosaic of retained paleopolyploid regions. Some regions appear to be highly conserved while other regions have diverged significantly. Large-scale "batch" reassembly of all 17 BACs combined showed that even the most homeologous BACs with upwards of 95% sequence identity resolve into their respective homeologous sequences. Potential assembly errors were generated by tandemly duplicated pentatricopeptide repeat containing genes and long simple sequence repeats. Analysis of a whole-genome shotgun assembly of 80,000 randomly chosen JGI-DOE sequence traces reveals some new soybean-specific repeat sequences.</p> <p>Conclusion</p> <p>This analysis investigated both the structure of the paleopolyploid soybean genome and the potential effects retained homeology will have on assembling the whole genome shotgun sequence. Based upon these results, homeologous regions similar to those characterized here will not cause major assembly issues.</p

miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ~22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation