Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
| Autor: | Benjamin L. Ebert, Anindita Roy, Barbara Zieger, Caleb A. Lareau, Marcin W. Wlodarski, Vijay G. Sankaran, Philip Ancliff, Namrata Gupta, Nour J. Abdulhay, Charlotte M. Niemeyer, Hanna T. Gazda, Jeffrey M. Verboon, Stacey Gabriel, Miriam Erlacher, Leif S. Ludwig, Xiaoli Mi, Esther A. Obeng, Rami Khoriaty, Claudia Fiorini, Jacob C. Ulirsch |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Zinc finger Genetics Mutation Immunology Intron GATA1 Biology medicine.disease_cause 03 medical and health sciences Exon 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis RNA splicing medicine Intronic Mutation Immunology and Allergy Dyserythropoietic anemia |
| DOI: | 10.1084/jem.20181625 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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