title: Paris-Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA-binding domain mutation in FLI1.
abstract: Hemizygous deletion of a variable region on chromosome 11q containing FLI1 causes an inherited platelet-related bleeding disorder in Paris-Trousseau thrombocytopenia and Jacobsen syndrome. These multisystem disorders are also characterized by heart anomalies, changes in facial structure, and intellectual disability. We have identified a consanguineous family with autosomal recessive inheritance of a bleeding disorder that mimics Paris-Trousseau thrombocytopenia but has no other features of the 11q23 deletion syndrome. Affected individuals in this family have moderate thrombocytopenia; absent collagen-induced platelet aggregation; and large, fused α-granules in 1% to 5% of circulating platelets. This phenotype was caused by a FLI1 homozygous c.970C>T-point mutation that predicts an arginine-to-tryptophan substitution in the conserved ETS DNA-binding domain of FLI1. This mutation caused a transcription defect at the promoter of known FLI1 target genes GP6, GP9, and ITGA2B, as measured by luciferase assay in HEK293 cells, and decreased the expression of these target proteins in affected members of the family as measured by Western blotting of platelet lysates. This kindred suggests abnormalities in FLI1 as causative of Paris-Trousseau thrombocytopenia and confirms the important role of FLI1 in normal platelet development.
authors: Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia; Northern Blood Research Centre, Kolling Institute of Medical Research.
authors: William S
authors: WS
authors: Stevenson
authors: Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia; Northern Blood Research Centre, Kolling Institute of Medical Research.
authors: David J
authors: DJ
authors: Rabbolini
authors: Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia; Northern Blood Research Centre, Kolling Institute of Medical Research.
authors: Lucinda
authors: L
authors: Beutler
authors: Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia; Northern Blood Research Centre, Kolling Institute of Medical Research.
authors: Qiang
authors: Q
authors: Chen
authors: Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia; Northern Blood Research Centre, Kolling Institute of Medical Research.
authors: Sara
authors: S
authors: Gabrielli
authors: School of Molecular Biosciences, The University of Sydney, Sydney, Australia; and.
authors: Joel P
authors: JP
authors: Mackay
authors: South Eastern Area Laboratory Services, Prince of Wales Hospital, Sydney, Australia.
authors: Timothy A
authors: TA
authors: Brighton
authors: Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia; Northern Blood Research Centre, Kolling Institute of Medical Research.
authors: Christopher M
authors: CM
authors: Ward
authors: Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia; Northern Blood Research Centre, Kolling Institute of Medical Research.
authors: Marie-Christine
authors: http://orcid.org/0000-0003-4795-1746
authors: MC
authors: Morel-Kopp
mesh_terms: D000595:Amino Acid Sequence; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D004247:DNA / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D005808:Genes, Recessive; D057809:HEK293 Cells; D006801:Humans; D054868:Jacobsen Distal 11q Deletion Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: C078433:FLI1 protein, human; D051789:Proto-Oncogene Protein c-fli-1; D004247:DNA