Tummala, H; Walne, AJ; Bewicke-Copley, F; Ellison, A; Pontikos, N; Bridger, MG; Rio-Machin, A; ... Dokal, I; + view all Tummala, H; Walne, AJ; Bewicke-Copley, F; Ellison, A; Pontikos, N; Bridger, MG; Rio-Machin, A; Sidhu, JK; Wang, J; Hasle, H; Fitzgibbon, J; Vulliamy, T; Dokal, I; - view fewer (2020) A frameshift variant in specificity protein 1 triggers superactivation of Sp1-mediated transcription in familial bone marrow failure. Proceedings of the National Academy of Sciences of the United States of America 10.1073/pnas.2002857117. (In press).

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Abstract

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.

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