ABSTRACT
SOX4 is a transcription factor with pleiotropic functions required for different developmental processes, such as corticogenesis. As with all SOX proteins, it contains a conserved high mobility group (HMG) and exerts its function via interaction with other transcription factors, such as POU3F2. Recently, pathogenic SOX4 variants have been identified in several patients who had clinical features overlapping with Coffin-Siris syndrome. In this study, we identified three novel variants in unrelated patients with intellectual disability, two of which were de novo (c.79G>T, p.Glu27*; c.182G>A p.Arg61Gln) and one inherited (c.355C>T, p.His119Tyr). All three variants affected the HMG box and were suspected to influence SOX4 function. We investigated the effects of these variants on transcriptional activation by co-expressing either wildtype (wt) or mutant SOX4 with its co-activator POU3F2 and measuring their activity in reporter assays. All variants abolished SOX4 activity. While our experiments provide further support for the pathogenicity of SOX4 loss-of-function (LOF) variants as a cause of syndromic intellectual disability (ID), our results also indicate incomplete penetrance associated with one variant. These findings will improve classification of novel, putatively pathogenic SOX4 variants.
Subject(s)
Abnormalities, Multiple , Intellectual Disability , SOXC Transcription Factors , Humans , Gene Expression Regulation , Intellectual Disability/genetics , Micrognathism/genetics , SOXC Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Circular RNAs (circRNAs) are regulators of processes like adipogenesis. Their expression can be modulated by SNPs. We analysed links between BMI-associated SNPs and circRNAs. First, we detected an enrichment of BMI-associated SNPs on circRNA genomic loci in comparison to non-significant variants. Analysis of sex-stratified GWAS data revealed that circRNA genomic loci encompassed more genome-wide significant BMI-SNPs in females than in males. To explore whether the enrichment is restricted to BMI, we investigated nine additional GWAS studies. We showed an enrichment of trait-associated SNPs in circRNAs for four analysed phenotypes (body height, chronic kidney disease, anorexia nervosa and autism spectrum disorder). To analyse the influence of BMI-affecting SNPs on circRNA levels in vitro, we examined rs4752856 located on hsa_circ_0022025. The analysis of heterozygous individuals revealed an increased level of circRNA derived from the BMI-increasing SNP allele. We conclude that genetic variation may affect the BMI partly through circRNAs.
Subject(s)
Autism Spectrum Disorder , RNA, Circular , Body Mass Index , Female , Humans , Male , Polymorphism, Single Nucleotide , RNA/metabolism , RNA, Circular/geneticsABSTRACT
Many plant genomes display high levels of repetitive sequences. The assembly of these complex genomes using short high-throughput sequence reads is still a challenging task. Underestimation or disregard of repeat complexity in these datasets can easily misguide downstream analysis. Detection of repetitive regions by k-mer counting methods has proved to be reliable. Easy-to-use applications utilizing k-mer counting are in high demand, especially in the domain of plants. We present Kmasker plants, a tool that uses k-mer count information as an assistant throughout the analytical workflow of genome data that is provided as a command-line and web-based solution. Beside its core competence to screen and mask repetitive sequences, we have integrated features that enable comparative studies between different cultivars or closely related species and methods that estimate target specificity of guide RNAs for application of site-directed mutagenesis using Cas9 endonuclease. In addition, we have set up a web service for Kmasker plants that maintains pre-computed indices for 10 of the economically most important cultivated plants. Source code for Kmasker plants has been made publically available at https://github.com/tschmutzer/kmasker. The web service is accessible at https://kmasker.ipk-gatersleben.de.
Subject(s)
Genome, Plant/genetics , Algorithms , Gene Editing , Genomics , RNA, Guide, Kinetoplastida/genetics , Sequence Analysis, DNA , SoftwareABSTRACT
The taxonomy of treatment goal themes of the Bern Inventory of Treatment Goals (BIT-T) is presented. The taxonomy was developed using 1,031 treatment goals of 298 outpatients at a university clinic. A first version of the taxonomy was constructed by cluster-analyzing eo-occurrence values computed from categorizations made by 22 therapists. Iterative revisions after several rating trials resulted in BIT-T Version 3.1. Categories at the highest of three levels of abstraction are coping with specific problems and symptoms (P), interpersonal goals (I), well-being and functioning (W), existential issues (E), and personal growth (G). In (re-)coding an extended sample of outpatient treatment goals, the BIT-T proved to have a good interrater reliability, identified differences between diagnostic groups, and showed meaningful relations to standardized intake measures. Applications of the taxonomy for research and practice purposes as well as possible consequences of the obtained first results are discussed.
