<em>GFI1B</em> mutation causes a new bleeding disorder with abnormal platelet function — The Association Specialists
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GFI1B mutation causes a new bleeding disorder with abnormal platelet function (286)

Marie-Christine Morel-Kopp 1 2 , William S Stevenson 1 2 , Qiang Chen 1 2 , Hai Po Liang 1 2 , Catherine J Bromhead 3 , Susan Wright , Rust Turakulov 4 , Ashley P Ng 5 6 , Andrew W Roberts 5 7 , Melanie Bahlo 3 8 , Christopher M Ward 1 2
  1. Northern Blood Research Centre - Kolling Institute, The University of Sydney, Sydney, NSW, Australia
  2. Haematology Department, Royal North Shore Hospital, Sydney, NSW, Australia
  3. Bioinformatics Division , The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  4. Bioinformatics Division, Australian Genome Research Facility, Melbourne, Victoria, Australia
  5. Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  6. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
  7. Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
  8. Department of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia

GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development, but previously unknown to be associated with human disease.

A four generation Australian family with a novel bleeding disorder was identified and characterized. All affected family members presented 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 only exhibit abnormal bleeding with surgery.

Genetic linkage analysis was used to localize the mutation causing the disease on chromosome 9. This region extended from 125 314 885 to 141 213 431 bp and contained 367 genes, spanning 31.3 cM. Massively parallel sequencing was performed on that region and a novel single nucleotide insertion in exon 7 of GFI1B, c.880-881insC, was identified leading to a frameshift mutation in the fifth zinc finger DNA-binding domain and premature stop codon. Both mutant and wild-type GFI1B transcripts are present in platelets from affected individuals. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript. We demonstrated a dominant negative transcriptional activity of the mutant protein as opposed to a haploinsufficiency mechanism. This mutation alters the transcriptional activity of the protein resulting in impaired intracellular trafficking and cell signalling, abnormal cytoskeleton, reduction in platelet a-granule content and aberrant expression of key platelet proteins.

GFI1B mutation represents a novel human bleeding disorder and the described phenotype identifies GFI1B as a critical transcription factor implicated in erythropoiesis and megakaryopoiesis which regulates a-granule production, platelet shape, number and function and causes an autosomal dominant bleeding disorder in humans.