GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

J Thromb Haemost. 2021 Sep;19(9):2287-2301. doi: 10.1111/jth.15412. Epub 2021 Jul 10.


Background: 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.

Objective: To extensively phenotype two pedigrees displaying different variants in the GATA1 gene and determine if GATA1 controls MYH10 expression levels, a key modulator of MK polyploidization.

Method: A total of 146 unrelated propositi with constitutional thrombocytopenia were screened on a multigene panel. We described the genotype-phenotype correlation in GATA1 variant carriers and investigated the effect of these novel variants on MYH10 transcription using 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. p.N206I localized in the N terminal zinc finger was associated, on the other hand, with severe thrombocytopenia (15G/L) in early life. High MYH10 levels were evidenced in platelets of GATA1 variant carriers. Analysis of MKs anti-GATA1 chromatin immunoprecipitation-sequencing data revealed two GATA1 binding sites, located in the 3' untranslated region and in intron 8 of the MYH10 gene. Luciferase reporter assays showed their respective role in the regulation of MYH10 gene expression. Both GATA1 variants significantly alter intron 8 driven MYH10 transcription.

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 polyploidization defect.

Keywords: GATA1; MYH10; downstream targets; functional variants; platelets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Platelets
  • GATA1 Transcription Factor* / genetics
  • Gene Silencing
  • Humans
  • Megakaryocytes*
  • Myosin Heavy Chains / genetics*
  • Nonmuscle Myosin Type IIB / genetics*
  • Thrombocytopenia* / genetics
  • Thrombopoiesis / genetics
  • Transcription Factors


  • GATA1 Transcription Factor
  • GATA1 protein, human
  • Transcription Factors
  • Nonmuscle Myosin Type IIB
  • nonmuscle myosin type IIB heavy chain
  • Myosin Heavy Chains