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Impaired human hematopoiesis due to a cryptic intronic splicing mutation

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Item Type:Article
Title:Impaired human hematopoiesis due to a cryptic intronic splicing mutation
Creators Name:Abdulhay, N.J. and Fiorini, C. and Verboon, J.M. and Ludwig, L.S. and Ulirsch, J.C. and Zieger, B. and Lareau, C.A. and Mi, X. and Roy, A. and Obeng, E.A. and Erlacher, M. and Gupta, N. and Gabriel, S.B. and Ebert, B.L. and Niemeyer, C.M. and Khoriaty, R.N. and Ancliff, P. and Gazda, H.T. and Wlodarski, M.W. and Sankaran, V.G.
Abstract:Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five-amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.
Keywords:Alternative Splicing, Congenital Dyserythropoietic Anemia, Exons, GATA1 Transcription Factor, Genetic Transcription, HEK293 Cells, Hematopoiesis, Hematopoietic Stem Cells, Introns, Missense Mutation, Myelodysplastic Syndromes, RNA Splice Sites, Transfection
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:1050-1060
Date:6 May 2019
Official Publication:https://doi.org/10.1084/jem.20181625
PubMed:View item in PubMed

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