A dominant-negative GFI1B mutation in the gray platelet syndrome
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
The New England journal of medicine. - Boston, Mass., 1928, currens
, p. 245-253
University of Antwerp
The gray platelet syndrome is a hereditary, usually autosomal recessive bleeding disorder caused by a deficiency of alpha granules in platelets. We detected a nonsense mutation in the gene encoding the transcription factor GFI1B (growth factor independent 1B) that causes autosomal dominant gray platelet syndrome. Both gray platelets and megakaryocytes had abnormal marker expression. In addition, the megakaryocytes had dysplastic features, and they were abnormally distributed in the bone marrow. The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity in a dominant-negative manner. Our studies show that GFI1B, in addition to being causally related to the gray platelet syndrome, is key to megakaryocyte and platelet development. A large family is described with gray platelet syndrome due to an autosomal dominant inheritance pattern related to a dominant-negative mutation in GFI1B. The mutation leads to a loss in gene repression during megakaryocyte development. Platelets are formed through fragmentation of megakaryocytes that reside in the bone marrow.(1),(2) Platelet alpha granules, which are by far the most abundant platelet organelles, store proteins that stimulate platelet adhesiveness, hemostasis, and wound healing.(3),(4) The gray platelet syndrome is an inherited bleeding disorder characterized by defective production of alpha granules.(5),(6) Patients with this syndrome have reduced numbers of larger-than-normal platelets, and on light microscopy these platelets have a typical gray appearance caused by the lack of alpha granules. For a final diagnosis, the lack of alpha granules must be confirmed by means of electron microscopy.(7) Clinically, ...