Thrombocytopenia and CD CD 34 expression is decoupled from α‐granule deficiency with mutation of the first growth factor‐independent 1B zinc finger

摘要

Essentials The phenotypes of different growth factor‐independent 1B (GFI1B) variants are not established. GFI1B variants produce heterogeneous clinical phenotypes dependent on the site of mutation. Mutation of the first non‐DNA‐binding zinc‐finger causes a mild platelet and clinical phenotype. GFI1B regulates the CD34 promoter; platelet CD34 expression is an indicator of GFI1B mutation. Summary Background Mutation of the growth factor‐independent 1B ( GFI 1B) fifth DNA ‐binding zinc‐finger domain causes macrothrombocytopenia and α‐granule deficiency leading to clinical bleeding. The phenotypes associated with GFI 1B variants disrupting non‐ DNA ‐binding zinc‐fingers remain uncharacterized. Objectives To determine the functional and phenotypic consequences of GFI 1B variants disrupting non‐ DNA ‐binding zinc‐finger domains. Methods The GFI 1B C168F variant and a novel GFI 1B c.2520 + 1_2520 + 8del GTGGGCAC splice variant were identified in four unrelated families. Phenotypic features, DNA ‐binding properties and transcriptional effects were determined and compared with those in individuals with a GFI 1B H294 fs mutation of the fifth DNA ‐binding zinc‐finger. Patient‐specific induced pluripotent stem cell (i PSC )‐derived megakaryocytes were generated to facilitate disease modeling. Results The DNA ‐binding GFI 1B variant C168F, which is predicted to disrupt the first non‐ DNA ‐binding zinc‐finger domain, is associated with macrothrombocytopenia without α‐granule deficiency or bleeding symptoms. A GFI 1B splice variant, c.2520 + 1_2520 + 8del GTGGGCAC , which generates a short GFI 1B isoform that lacks non‐ DNA ‐binding zinc‐fingers 1 and 2, is associated with increased platelet CD 34 expression only, without quantitative or morphologic platelet abnormalities. GFI 1B represses the CD 34 promoter, and this repression is attenuated by different GFI 1B zinc‐finger mutations, suggesting that deregulation of CD 34 expression occurs at a direct transcriptional level. Patient‐specific i PSC ‐derived megakaryocytes phenocopy these observations. Conclusions Disruption of GFI 1B non‐ DNA ‐binding zinc‐finger 1 is associated with mild to moderate thrombocytopenia without α‐granule deficiency or bleeding symptomatology, indicating that the site of GFI 1B mutation has important phenotypic implications. Platelet CD 34 expression appears to be a common feature of perturbed GFI 1B function, and may have diagnostic utility.