Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations Journal Article


Authors: Pangallo, J.; Kiladjian, J. J.; Cassinat, B.; Renneville, A.; Taylor, J.; Polaski, J. T.; North, K.; Abdel-Wahab, O.; Bradley, R. K.
Article Title: Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations
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 carries 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 used 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 2 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. © 2020 by The American Society of Hematology.
Journal Title: Blood
Volume: 135
Issue: 13
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2020-03-26
Start Page: 1032
End Page: 1043
Language: English
DOI: 10.1182/blood.2019002894
PUBMED: 31961934
PROVIDER: scopus
PMCID: PMC7099330
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Justin   Taylor
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