Premium
GFI 1B mutation causes a bleeding disorder with abnormal platelet function
Author(s) -
Stevenson W. S.,
MorelKopp M.C.,
Chen Q.,
Liang H. P.,
Bromhead C. J.,
Wright S.,
Turakulov R.,
Ng A. P.,
Roberts A. W.,
Bahlo M.,
Ward C. M.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12368
Subject(s) - frameshift mutation , mutation , biology , platelet disorder , megakaryocyte , platelet , genetics , mutant protein , blood platelet disorders , mutant , phenotype , bleeding time , cancer research , gene , immunology , stem cell , progenitor cell , platelet aggregation
Summary Background GFI 1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease. Methods A family with a novel bleeding disorder was identified and characterized. Genetic linkage analysis and massively parallel sequencing were used to localize the mutation causing the disease phenotype on chromosome 9. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript. Results We have identified a family with an autosomal dominant bleeding disorder associated with macrothrombocytopenia, red cell anisopoikilocytosis, and platelet dysfunction. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other family members exhibit only abnormal bleeding with surgery. A single nucleotide insertion was identified in GFI 1B that predicts a frameshift mutation in the fifth zinc finger DNA ‐binding domain. This mutation alters the transcriptional activity of the protein, resulting in a reduction in platelet α‐granule content and aberrant expression of key platelet proteins. Conclusions GFI 1B mutation represents a novel human bleeding disorder, and the described phenotype identifies GFI 1B as a critical regulator of platelet shape, number, and function.