CRISPR Diagnostics for Quantification and Rapid Diagnosis of Myotonic Dystrophy Type 1 Repeat Expansion Disorders.

Repeat expansion disorders, exemplified by myotonic dystrophy type 1 (DM1), present challenges in diagnostic quantification because of the variability and complexity of repeat lengths. Traditional diagnostic methods, including PCR and Southern blotting, exhibit limitations in sensitivity and specificity, necessitating the development of innovative approaches for precise and rapid diagnosis. Here, we introduce a CRISPR-based diagnostic method, REPLICA (peat-rimed ocating of nherited disease by s3), for the quantification and rapid diagnosis of DM1.

Functional and dynamic profiling of transcript isoforms reveals essential roles of alternative splicing in interferon response.

Type I interferon (IFN-I) plays an important role in the innate immune response through inducing IFN-I-stimulated genes (ISGs). However, how alternative splicing (AS) events, especially over time, affect their function remains poorly understood. We generated an annotation (113,843 transcripts) for IFN-I-stimulated human B cells called isoISG using high-accuracy long-read sequencing data from PacBio Sequel II/IIe.

Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms.

Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer's disease locus.

Humoral responses are enhanced by facilitating B cell viability by Fcrl5 overexpression in B cells.

B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed in naive B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses.

Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling.

Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP.

Uncovering the Localization and Function of a Novel Read-Through Transcript ''.

Recent advancements in genome analysis technology have revealed the presence of read-through transcripts in which transcription continues by skipping the polyA signal. We here identified and characterized a new read-through transcript, . With cDNA amplification from THP-1 cells, the product was successfully generated.

Upregulated Fcrl5 disrupts B cell anergy and causes autoimmune disease.

B cell anergy plays a critical role in maintaining self-tolerance by inhibiting autoreactive B cell activation to prevent autoimmune diseases. Here, we demonstrated that Fc receptor-like 5 (Fcrl5) upregulation contributes to autoimmune disease pathogenesis by disrupting B cell anergy. Fcrl5-a gene whose homologs are associated with human autoimmune diseases-is highly expressed in age/autoimmunity-associated B cells (ABCs), an autoreactive B cell subset.

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study.

Introduction: Adolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested.

Rare germline variants in pancreatic cancer and multiple primary cancers: an autopsy study.

Background: There is a lack of information on rare germline variants of pancreatic cancer-predisposing genes. Risk genes for multiple primary cancers may overlap with those for pancreatic cancer.

Methods: A retrospective study of autopsy cases with a negative family history in the Japanese single nucleotide polymorphism for geriatric research database examined rare germline variants in the protein-coding regions of 61 genes.

Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups.

Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci.

Splicing quantitative trait loci (sQTLs) are one of the major causal mechanisms in genome-wide association study (GWAS) loci, but their role in disease pathogenesis is poorly understood. One reason is the complexity of alternative splicing events producing many unknown isoforms. Here, we propose two approaches, namely integration and selection, for this complexity by focusing on protein-structure of isoforms.

Utility of tissue-specific gene expression scores for gene prioritization in Mendelian diseases.

In genetic testing of Mendelian diseases, it is a bioinformatics challenge to effectively prioritize disease-causing candidate genes listed from massively parallel sequencing. Tissue specificity of the gene expression levels may give a clue because it may reflect tissue-specific disease manifestation. However, considering poor correlations between mRNA and protein expression in some genes, it is not clear whether transcriptomics- or proteomics-based tissue specificity should be used to prioritize candidate genes.

Combined plasma metabolomic and transcriptomic analysis identify histidine as a biomarker and potential contributor in SLE pathogenesis.

Objectives: To investigate metabolite alterations in the plasma of SLE patients to identify novel biomarkers and provide insight into SLE pathogenesis.

Methods: Patients with SLE (n = 41, discovery cohort and n = 37, replication cohort), healthy controls (n = 30 and n = 29) and patients with RA (n = 19, disease control) were recruited. Metabolic profiles of the plasma samples were analysed using liquid chromatography-time-of-flight mass spectrometry and capillary electrophoresis-time-of-flight mass spectrometry.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

Objective: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis.

Methods: We built gene expression predictive models in blood B cells, CD4 and CD8 T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals.

47XXY and 47XXX in Scleroderma and Myositis.

Objective: We undertook this study to examine the X chromosome complement in participants with systemic sclerosis (SSc) as well as idiopathic inflammatory myopathies.

Methods: The participants met classification criteria for the diseases. All participants underwent single-nucleotide polymorphism typing.

Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus.

Objective: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease. While the long-term prognosis has greatly improved, better long-term survival is still necessary. The type I interferon (IFN) signature, a prominent feature of SLE, is not an ideal therapeutic target or outcome predictor.

Association of Polygenic Risk Scores With Radiographic Progression in Patients With Rheumatoid Arthritis.

Objective: To investigate whether polygenic risk scores obtained using data from a genome-wide association study (GWAS) of rheumatoid arthritis (RA) susceptibility can be predictors of radiographic progression.

Methods: We constructed polygenic risk scores using GWAS summary data on associations of single-nucleotide polymorphisms with RA susceptibility. The polygenic risk scores were stratified into quintiles based on levels of significance (ranging from top quintile of polygenic risk scores to bottom quintile).

Anti-Double-Stranded DNA Antibodies Recognize DNA Presented on HLA Class II Molecules of Systemic Lupus Erythematosus Risk Alleles.

Objective: Specific HLA class II alleles are associated with susceptibility to systemic lupus erythematosus (SLE). The role of HLA class II molecules in SLE pathogenesis remains unclear, although anti-DNA antibodies are specific to SLE and correlate with disease activity. We previously demonstrated that misfolded proteins bound to HLA class II molecules are specific targets for the autoantibodies produced in autoimmune diseases.

Polygenic Risk Score of Adolescent Idiopathic Scoliosis for Potential Clinical Use.

Adolescent idiopathic scoliosis (AIS) is a common disease causing three-dimensional spinal deformity in as many as 3% of adolescents. Development of a method that can accurately predict the onset and progression of AIS is an immediate need for clinical practice. Because the heritability of AIS is estimated as high as 87.

Eight novel susceptibility loci and putative causal variants in atopic dermatitis.

Background: Atopic dermatitis (AD) is the most common allergic disease in the world. While genetic components play critical roles in its pathophysiology, a large proportion of its genetic background is still unexplored.

Objectives: This study sought to illuminate the genetic associations with AD using genome-wide association study (GWAS) and its downstream analyses.

Lupus Susceptibility Region Containing CDKN1B rs34330 Mechanistically Influences Expression and Function of Multiple Target Genes, Also Linked to Proliferation and Apoptosis.

Objective: In a recent genome-wide association study, a significant genetic association between rs34330 of CDKN1B and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant.

Methods: We performed an allelic association analysis in patients with SLE, followed by a meta-analysis assessing genome-wide association data across 11 independent cohorts (n = 28,872).