GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

Objective GATA1 is an essential transcription factor for both polyploidization and megakaryocyte (MK) differentiation. The polyploidization defect observed in GATA1 variant carriers is not well understood.

Material and Methods 146 unrelated propositi with constitutional thrombocytopenia were screened on a multigene panel. Two novel GATA1 variants were identified in three boys from two unrelated families. We described the genotype-phenotype correlation, and investigated the effect of GATA1 variants on transcription assays using MYH10 luciferase constructs

Results The clinical profile associated with the p.L268M variant localized in the C terminal Zinc finger was unusual in that the patient displayed bleeding and severe platelet aggregation defects without early-onset thrombocytopenia. High MYH10 levels were evidenced in platelets of GATA1 variant carriers. Analysis of MKs anti-GATA1 ChIP-sequencing data revealed two GATA1 binding sites (BS), located in the 3ʹ untranslated region and in intron 8 of the MYH10 gene. Luciferase reporter assays showed their role in the regulation of MYH10 gene expression. Significantly decreased transcriptional activation was shown for the two GATA1 variants.

Conclusion The discovery of an association between MYH10 and GATA1 is a novel one. Overall, this study suggests that impaired MYH10 silencing via an intronic regulatory element is the most likely cause of GATA1-related thrombocytopenia.

Publication History

Article published online:
18 June 2021