Dominant-negative GFI1B mutation in Gray Platelet Syndrome

Reijden, Bert van der

Research teams from Radboudumc, Antwerp University, Belgium and University Hospital Essen, Germany, led by Bert van der Reijden from the Lab of Hematology, Radboudumc have identified Growth Factor Independent 1B (GFI1B) as a causative gene in autosomal dominant Gray Platelet Syndrome, according to study findings presented at the late breaking abstract session at the American Society of Hematology Annual Meeting and published in New England Journal of Medicine on line (December 2013).

Patients with Gray Platelet Syndrome - a hereditary bleeding disorder - exhibit reduced numbers of platelets, which are enlarged with a gray appearance caused by the shortage of alpha-granules. Van der Reijden and colleagues examined a large family with an autosomal dominant type of Gray Platelet Syndrome characterized by moderate to severe bleeding complications. In addition, to gray platelets the megakaryocytes had dysplastic features, and they were abnormally distributed in the bone marrow. Genetic linkage analysis and targeted sequencing identified a nonsense mutation in the GFI1Bgene that completely cosegregated with the disease. GFI1B functions as transcriptional repressor. The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity in a dominant-negative manner. Additional studies showed that megakaryocyte colony-forming cells were significantly more frequent in patient bone marrow vs. controls and that patient-derived megakaryocyte colonies were significantly larger compared with controls. The research teams also showed abnormal marker expression on affected megakaryocytes and platelets, exemplified by high expression of the stem cell marker CD34. Together, these studies show that GFI1B, in addition to being causally related to the Gray Platelet Syndrome, is key to normal megakaryocyte and platelet development.

Monteferrario D, Bolar NA, Marneth AE, Hebeda KM, Bergevoet SM, Veenstra H, Laros-van Gorkom BA, Mackenzie MA, Khandanpour C, Botezatu L, Fransen E, Van Camp G, Duijnhouwer AL, Salemink S, Willemsen B, Huls G, Preijers F, Van Heerde W, Jansen JH, Kempers MJ, Loeys BL, Van Laer L, Van der Reijden BA. A Dominant-Negative GFI1B Mutation in the Gray Platelet Syndrome. N Engl J Med. 2013 Dec 10. [Epub ahead of print] PubMed PMID: 24325358.

Bert van der Reijden, Dept of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.

Interview Bert van der Reijden talking to Ariez Publishing (Dutch)


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