Spliceosomal helicases DDX41/SACY-1 and PRP22/MOG-5 both contribute to proofreading against proximal 3′ splice site usage

Alternative splicing (AS) is emerging as an important regulatory process for complex biological processes. Transcriptomic studies therefore commonly involve the identification and quantification of alternative processing events, but the need for predicting the functional consequences of changes to the relative inclusion of alternative events remains largely unaddressed. Many tools exist for the former task, albeit each constrained to its own event type definitions. Few tools exist for the latter task; each with significant limitations. To address these issues we developed junctionCounts, which captures both simple and complex pairwise AS events and quantifies them with straightforward exon-exon and exon-intron junction reads in RNA-seq data, performing competitively among similar tools in terms of sensitivity, false discovery rate and quantification accuracy. Its partner utility, cdsInsertion, identifies transcript coding sequence (CDS) information via in silico translation from annotated start codons, including the presence of premature termination codons. Finally, findSwitchEvents connects AS events with CDS information to predict the impact of individual events to the isoform-level CDS. We used junctionCounts to characterize splicing dynamics and NMD regulation during neuronal differentiation across four primates, demonstrating junctionCounts’ capacity to robustly characterize AS in a variety of organisms and to predict its effect on mRNA isoform fate.

show abstract

Germline DDX41 mutations in myeloid neoplasms: the current clinical and molecular understanding

Kida,

Chlon

2024

Current Opinion in Hematology

View full text Add to dashboard Cite

Purpose of review DDX41 mutations are the most common cause of germline predisposition to adult-onset myeloid neoplasms. The unique mutational landscape and clinical features indicate a distinct molecular pathogenesis, but the precise mechanism by which DDX41 mutations cause disease is poorly understood, owing to the multitude of DDX41 functions. In this review, we will update DDX41's known functions, present unique clinical features and treatment considerations, and summarize the current understanding of the molecular pathogenesis of the disease. Recent findings Large cohort studies have revealed that germline DDX41 variants are heterozygous and predominantly loss-of-function. Acquired mutation of the contralateral DDX41 allele, typically R525H, is present in more than half of patients at disease onset, which occurs after age 50. DDX41 is essential for hematopoiesis and has versatile functions in RNA metabolism and innate immune sensing. Experimental models have suggested that innate immune activation downstream of defects in R-loop resolution and ribosome biogenesis plays a key role in the pathogenesis. Summary While intensive investigations unveiled a strong genotype–phenotype relationship, the optimal therapeutic approach and long-term outcome are undefined. There is an urgent need to scrutinize the patients at single cell and multiomics level and to advance experimental animal and human models to fully elucidate the molecular pathogenesis.

show abstract

Spliceosomal helicases DDX41/SACY-1 and PRP22/MOG-5 both contribute to proofreading against proximal 3′ splice site usage

Cited by 4 publications

References 38 publications

Understanding the dynamic design of the spliceosome

Understanding the dynamic design of the spliceosome

junctionCounts: comprehensive alternative splicing analysis and prediction of isoform-level impacts to the coding sequence

Germline DDX41 mutations in myeloid neoplasms: the current clinical and molecular understanding

Contact Info

Product

Resources

About