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Enrichment of FLI1and RUNX1mutations in families with excessive bleeding and platelet dense granule secretion defects

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.
Source :
Blood; December 2013, Vol. 122 Issue: 25 p4090-4093, 4p
Publication Year :
2013

Abstract

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 FLI1and 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 FLI1alterations 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 FLI1and RUNX1may be common in patients with platelet dense granule secretion defects and mild thrombocytopenia.

Details

Language :
English
ISSN :
00064971 and 15280020
Volume :
122
Issue :
25
Database :
Supplemental Index
Journal :
Blood
Publication Type :
Periodical
Accession number :
ejs56962660
Full Text :
https://doi.org/10.1182/blood-2013-06-506873