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

Stockley, J, Morgan, N, Bem, D, Lowe, G, Lordkipanidze, M, Dawood, B, Simpson, M, Macfarlane, K, Horner, K, Leo, V, Talks, K, Motwani, J, Wilde, J, Collins, Peter William ORCID: https://orcid.org/0000-0002-6410-1324, Makris, M, Watson, S and Daly, M 2013. Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects. Blood 122 (25) , pp. 4090-4093. 10.1182/blood-2013-06-506873

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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 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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	American Society of Hematology
ISSN:	0006-4971
Date of Acceptance:	12 December 2013
Last Modified:	23 Oct 2022 13:18
URI:	https://orca.cardiff.ac.uk/id/eprint/110261

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