A frameshift variant in specificity protein 1 triggers superactivation of Sp1-mediated transcription in familial bone marrow failure

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DOI

  • Hemanth Tummala, Queen Mary University of London
  • ,
  • Amanda J. Walne, Queen Mary University of London
  • ,
  • Findlay Bewicke-Copley, Queen Mary University of London
  • ,
  • Alicia Ellison, Queen Mary University of London
  • ,
  • Nikolas Pontikos, Queen Mary University of London
  • ,
  • Maria G. Bridger, Queen Mary University of London
  • ,
  • Ana Rio-Machin, Queen Mary University of London
  • ,
  • Jasmin K. Sidhu, Queen Mary University of London
  • ,
  • Jun Wang, Queen Mary University of London
  • ,
  • Henrik Hasle
  • Jude Fitzgibbon, Queen Mary University of London
  • ,
  • Tom Vulliamy, Queen Mary University of London
  • ,
  • Inderjeet Dokal, Queen Mary University of London

Inherited bone marrow failure (BMF) syndromes are a heterogeneous group of diseases characterized by defective hematopoiesis and often predisposing to myelodysplastic syndrome (MDS) and acute myelogenous leukemia. We have studied a large family consisting of several affected individuals with hematologic abnormalities, including one family member who died of acute leukemia. By whole-exome sequencing, we identified a novel frameshift variant in the ubiquitously expressed transcription factor specificity protein 1 (SP1). This heterozygous variant (c.1995delA) truncates the canonical Sp1 molecule in the highly conserved C-terminal DNA-binding zinc finger domains. Transcriptomic analysis and gene promoter characterization in patients' blood revealed a hypermorphic effect of this Sp1 variant, triggering superactivation of Sp1-mediated transcription and driving significant up-regulation of Sp1 target genes. This familial genetic study indicates a central role for Sp1 in causing autosomal dominant transmission of BMF, thereby confirming its critical role in hematopoiesis in humans.

OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind117
Nummer29
Sider (fra-til)17151-17155
Antal sider5
ISSN0027-8424
DOI
StatusUdgivet - jul. 2020

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