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

Inherited bone marrow failure (BMF) syndromes are a heterogeneous group of diseases characterised by defective hematopoiesis and often predispose to myelodysplastic syndrome (MDS) and acute myeloid leukemia. We have studied a large family consisting of several affected individuals with hematological 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. Functional characterisation of the truncated Sp1 molecule revealed compromised DNA binding ability and educed stability. Transcriptomic analysis and gene promoter characterisation in patients’ blood revealed a hypermorphic effect of this Sp1 variant, triggering superactivation of Sp1-mediated transcription and driving a significant upregulation of Sp1 target genes. his 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. Examination of mRNA profiles from a family with mutation of SP1