Kozyra, EJ;
Pastor, VB;
Lefkopoulos, S;
Sahoo, SS;
Busch, H;
Voss, RK;
Erlacher, M;
... Wlodarski, MW; + view all
(2020)
SynonymousGATA2mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency.
Leukemia
10.1038/s41375-020-0899-5.
(In press).
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Abstract
Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.
| Type: | Article |
|---|---|
| Title: | SynonymousGATA2mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41375-020-0899-5 |
| Publisher version: | https://doi.org/10.1038/s41375-020-0899-5 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Oncology, Hematology, WORLD-HEALTH-ORGANIZATION, SYNONYMOUS MUTATIONS, MYELOID NEOPLASMS, LEUKEMIA, DIFFERENTIATION, CLASSIFICATION, TRANSCRIPTION, EXPRESSION, REVISION, ABSENCE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10105508 |
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