GSE152262 A frameshift variant in the specificity protein 1 triggers superactivation of Sp1-mediated transcription in familial bone marrow failure

Contributors : Hemanth Tummala ; Tom Vulliamy ; Inderjeet DokalSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensInherited 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 c onfirming its critical role in hematopoiesis in humans.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research