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Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations
- Source :
- Blood. 135(13)
- Publication Year :
- 2019
-
Abstract
- Genes encoding the RNA splicing factors SF3B1, SRSF2, and U2AF1 are subject to frequent missense mutations in clonal hematopoiesis and diverse neoplastic diseases. Most "spliceosomal" mutations affect specific hotspot residues, resulting in splicing changes that promote disease pathophysiology. However, a subset of patients carry spliceosomal mutations that affect non-hotspot residues, whose potential functional contributions to disease are unstudied. Here, we undertook a systematic characterization of diverse rare and private spliceosomal mutations to infer their likely disease relevance. We utilized isogenic cell lines and primary patient materials to discover that 11 of 14 studied rare and private mutations in SRSF2 and U2AF1 induced distinct splicing alterations, including partially or completely phenocopying the alterations in exon and splice site recognition induced by hotspot mutations or driving "dual" phenocopies that mimicked two co-occurring hotspot mutations. Our data suggest that many rare and private spliceosomal mutations contribute to disease pathogenesis and illustrate the utility of molecular assays to inform precision medicine by inferring the potential disease relevance of newly discovered mutations.
- Subjects :
- 0301 basic medicine
RNA Splicing Factors
RNA Splicing
Immunology
Penetrance
Biology
Gene mutation
Biochemistry
03 medical and health sciences
Exon
0302 clinical medicine
Cell Line, Tumor
Missense mutation
Humans
Gene
Genetic Association Studies
Genetics
Phenocopy
Gene Expression Profiling
Computational Biology
Cell Biology
Hematology
Exons
Isogenic human disease models
030104 developmental biology
Phenotype
RNA splicing
Mutation
Spliceosomes
RNA Splice Sites
Transcriptome
030215 immunology
Subjects
Details
- ISSN :
- 15280020
- Volume :
- 135
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....a8d1e9090efb11452006d2faba2e2586