Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects

We analyzed candidate platelet function disorder genes in 13 index cases with a history of excessive bleeding in association with a significant reduction in dense granule secretion and impaired aggregation to a panel of platelet agonists. Five of the index cases also had mild thrombocytopenia. Heter...

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Bibliographic Details
Published in:Blood 2013-12, Vol.122 (25), p.4090-4093
Main Authors: Stockley, Jacqueline, Morgan, Neil V., Bem, Danai, Lowe, Gillian C., Lordkipanidzé, Marie, Dawood, Ban, Simpson, Michael A., Macfarlane, Kirsty, Horner, Kevin, Leo, Vincenzo C., Talks, Katherine, Motwani, Jayashree, Wilde, Jonathan T., Collins, Peter W., Makris, Michael, Watson, Steve P., Daly, Martina E.
Format: Article
Language:English
Subjects:
Blood Platelets
Brief Report
Core Binding Factor Alpha 2 Subunit - genetics
Core Binding Factor Alpha 2 Subunit - metabolism
Family
Female
Haploinsufficiency
Hemorrhage - genetics
Hemorrhage - metabolism
Humans
Male
Mutation
Platelets and Thrombopoiesis
Proto-Oncogene Protein c-fli-1 - genetics
Proto-Oncogene Protein c-fli-1 - metabolism
Secretory Pathway - genetics
Secretory Vesicles - genetics
Secretory Vesicles - metabolism
Thrombocytopenia - genetics
Thrombocytopenia - metabolism
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Summary:We analyzed candidate platelet function disorder genes in 13 index cases with a history of excessive bleeding in association with a significant reduction in dense granule secretion and impaired aggregation to a panel of platelet agonists. Five of the index cases also had mild thrombocytopenia. Heterozygous alterations in FLI1 and RUNX1, encoding Friend leukemia integration 1 and RUNT-related transcription factor 1, respectively, which have a fundamental role in megakaryocytopoeisis, were identified in 6 patients, 4 of whom had mild thrombocytopenia. Two FLI1 alterations predicting p.Arg337Trp and p.Tyr343Cys substitutions in the FLI1 DNA-binding domain abolished transcriptional activity of FLI1. A 4-bp deletion in FLI1, and 2 splicing alterations and a nonsense variation in RUNX1, which were predicted to cause haploinsufficiency of either FLI1 or RUNX1, were also identified. Our findings suggest that alterations in FLI1 and RUNX1 may be common in patients with platelet dense granule secretion defects and mild thrombocytopenia. Key Points
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2013-06-506873