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Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation

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. He...

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Autores principales: Abdulhay, Nour J., Fiorini, Claudia, Verboon, Jeffrey M., Ludwig, Leif S., Ulirsch, Jacob C., Zieger, Barbara, Lareau, Caleb A., Mi, Xiaoli, Roy, Anindita, Obeng, Esther A., Erlacher, Miriam, Gupta, Namrata, Gabriel, Stacey B., Ebert, Benjamin L., Niemeyer, Charlotte M., Khoriaty, Rami N., Ancliff, Philip, Gazda, Hanna T., Wlodarski, Marcin W., Sankaran, Vijay G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504223/
https://www.ncbi.nlm.nih.gov/pubmed/30914438
http://dx.doi.org/10.1084/jem.20181625
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author Abdulhay, Nour J.
Fiorini, Claudia
Verboon, Jeffrey M.
Ludwig, Leif S.
Ulirsch, Jacob C.
Zieger, Barbara
Lareau, Caleb A.
Mi, Xiaoli
Roy, Anindita
Obeng, Esther A.
Erlacher, Miriam
Gupta, Namrata
Gabriel, Stacey B.
Ebert, Benjamin L.
Niemeyer, Charlotte M.
Khoriaty, Rami N.
Ancliff, Philip
Gazda, Hanna T.
Wlodarski, Marcin W.
Sankaran, Vijay G.
author_facet Abdulhay, Nour J.
Fiorini, Claudia
Verboon, Jeffrey M.
Ludwig, Leif S.
Ulirsch, Jacob C.
Zieger, Barbara
Lareau, Caleb A.
Mi, Xiaoli
Roy, Anindita
Obeng, Esther A.
Erlacher, Miriam
Gupta, Namrata
Gabriel, Stacey B.
Ebert, Benjamin L.
Niemeyer, Charlotte M.
Khoriaty, Rami N.
Ancliff, Philip
Gazda, Hanna T.
Wlodarski, Marcin W.
Sankaran, Vijay G.
author_sort Abdulhay, Nour J.
collection PubMed
description 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.
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spelling pubmed-65042232019-11-06 Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation Abdulhay, Nour J. Fiorini, Claudia Verboon, Jeffrey M. Ludwig, Leif S. Ulirsch, Jacob C. Zieger, Barbara Lareau, Caleb A. Mi, Xiaoli Roy, Anindita Obeng, Esther A. Erlacher, Miriam Gupta, Namrata Gabriel, Stacey B. Ebert, Benjamin L. Niemeyer, Charlotte M. Khoriaty, Rami N. Ancliff, Philip Gazda, Hanna T. Wlodarski, Marcin W. Sankaran, Vijay G. J Exp Med Research Articles 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. Rockefeller University Press 2019-05-06 2019-03-26 /pmc/articles/PMC6504223/ /pubmed/30914438 http://dx.doi.org/10.1084/jem.20181625 Text en © 2019 Abdulhay et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Abdulhay, Nour J.
Fiorini, Claudia
Verboon, Jeffrey M.
Ludwig, Leif S.
Ulirsch, Jacob C.
Zieger, Barbara
Lareau, Caleb A.
Mi, Xiaoli
Roy, Anindita
Obeng, Esther A.
Erlacher, Miriam
Gupta, Namrata
Gabriel, Stacey B.
Ebert, Benjamin L.
Niemeyer, Charlotte M.
Khoriaty, Rami N.
Ancliff, Philip
Gazda, Hanna T.
Wlodarski, Marcin W.
Sankaran, Vijay G.
Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
title Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
title_full Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
title_fullStr Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
title_full_unstemmed Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
title_short Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
title_sort impaired human hematopoiesis due to a cryptic intronic gata1 splicing mutation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504223/
https://www.ncbi.nlm.nih.gov/pubmed/30914438
http://dx.doi.org/10.1084/jem.20181625
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