Impaired human hematopoiesis due to a cryptic intronic
| Autor: | Nour J, Abdulhay, Claudia, Fiorini, Jeffrey M, Verboon, Leif S, Ludwig, Jacob C, Ulirsch, Barbara, Zieger, Caleb A, Lareau, Xiaoli, Mi, Anindita, Roy, Esther A, Obeng, Miriam, Erlacher, Namrata, Gupta, Stacey B, Gabriel, Benjamin L, Ebert, Charlotte M, Niemeyer, Rami N, Khoriaty, Philip, Ancliff, Hanna T, Gazda, Marcin W, Wlodarski, Vijay G, Sankaran |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Transcription Genetic Mutation Missense Brief Definitive Report Exons Hematopoietic Stem Cells Transfection Introns Hematopoiesis Alternative Splicing HEK293 Cells Myelodysplastic Syndromes Humans GATA1 Transcription Factor RNA Splice Sites Child Research Articles Anemia Dyserythropoietic Congenital |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | Abdulhay et al. report that an intronic genetic variant alters GATA1 splicing and presents as a distinct form of dyserythropoietic anemia in two unrelated patients. Functional studies demonstrate that the novel GATA1 isoform lacks observable activity and leads to a decrease in wild-type GATA1 levels in affected individuals. 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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