biostudies-literatureTummala HMedical Research CouncilBlood Cancer UK17151-17155https://www.ebi.ac.uk/biostudies/studies/S-EPMC7382244biostudies-literatureUnknown117(29)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 (<i>SP1</i>). 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 variProceedings of the National Academy of Sciences of the United States of AmericaA frameshift variant in specificity protein 1 triggers superactivation of Sp1-mediated transcription in familial bone marrow failure.PMC738224414032MR/P018440/1Pontikos NSidhu JKEllison ABridger MGWang JRio-Machin ATummala HFitzgibbon JHasle HBewicke-Copley FDokal IWalne AJVulliamy TfalseA frameshift variant in 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 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 (<i>SP1</i>). 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 vari2020-01-01T00:00:00Z2020 Jul2026-05-04T03:43:34.165Z2020-11-07T11:38:24ZS-EPMC73822443263626810.1073/pnas.2002857117