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Journal Article

Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency

MPS-Authors

Lefkopoulos,  Stylianos
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Dereka,  Marta
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Trompouki,  Eirini
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Kozyra, E. J., Pastor, V. B., Lefkopoulos, S., Sahoo, S. S., Busch, H., Voss, R. K., et al. (2020). Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency. Leukemia: the Journal of Normal and Malignant Hemopoiese; Official Journal of the Leukemia Research Fund U.K., 34, 2673-2687.


Cite as: http://hdl.handle.net/21.11116/0000-0007-DCBE-C
Abstract
eficiency 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.