Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency
Autor: | Matthew Collin, Dirk Lebrecht, Eirini Trompouki, Emilia J Kozyra, Brigitte Strahm, Valerie de Haas, Sushree S. Sahoo, Owen P. Smith, Riccardo Masetti, Christian Flotho, Charlotte M. Niemeyer, Marta Derecka, Marco Tartaglia, Markus Schmugge, Krisztián Kállay, Rebecca K Voss, Henrik Hasle, Miriam Erlacher, Christian Klemann, Gudrun Göhring, Ester Mejstrikova, Marek Ussowicz, Hauke Busch, Preeti Singh, Barbara De Moerloose, Enikoe Amina Szvetnik, Marcin W. Wlodarski, Patrick Metzger, Lucia Pedace, Shinsuke Hirabayashi, Michael Dworzak, Emma C. Morris, Albert Català, Ramunė Pasaulienė, Jan Starý, Stylianos Lefkopoulos, Franco Locatelli, Victor B Pastor, Melanie Boerries |
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Přispěvatelé: | Kozyra E.J., Pastor V.B., Lefkopoulos S., Sahoo S.S., Busch H., Voss R.K., Erlacher M., Lebrecht D., Szvetnik E.A., Hirabayashi S., Pasauliene R., Pedace L., Tartaglia M., Klemann C., Metzger P., Boerries M., Catala A., Hasle H., de Haas V., Kallay K., Masetti R., De Moerloose B., Dworzak M., Schmugge M., Smith O., Stary J., Mejstrikova E., Ussowicz M., Morris E., Singh P., Collin M., Derecka M., Gohring G., Flotho C., Strahm B., Locatelli F., Niemeyer C.M., Trompouki E., Wlodarski M.W. |
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Male
Cancer Research GATA2 Deficiency VARIANT WORLD-HEALTH-ORGANIZATION GATA-2 Exon Genetics research Medicine and Health Sciences MDS TRANSCRIPTION Child Exome Genetics GATA2 RNA Genetic disorder Hematology ABSENCE REVISION GATA2 Transcription Factor DIFFERENTIATION Phenotype Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA Oncology Child Preschool RNA splicing Female Synonymous substitution Haematological diseases EXPRESSION Silent mutation Adult Heterozygote Adolescent Biology CLASSIFICATION Article Young Adult Germline mutation GATA2 mutations children myelodysplastic syndromes medicine Humans Genetic Predisposition to Disease MYELOID NEOPLASMS Genetic Association Studies Germ-Line Mutation Silent Mutation Immunologic Deficiency Syndromes medicine.disease Myelodysplastic Syndromes LEUKEMIA |
Zdroj: | Leukemia Kozyra, E J, Pastor, V B, Lefkopoulos, S, Sahoo, S S, Busch, H, Voss, R K, Erlacher, M, Lebrecht, D, Szvetnik, E A, Hirabayashi, S, Pasaulienė, R, Pedace, L, Tartaglia, M, Klemann, C, Metzger, P, Boerries, M, Catala, A, Hasle, H, de Haas, V, Kállay, K, Masetti, R, De Moerloose, B, Dworzak, M, Schmugge, M, Smith, O, Starý, J, Mejstrikova, E, Ussowicz, M, Morris, E, Singh, P, Collin, M, Derecka, M, Göhring, G, Flotho, C, Strahm, B, Locatelli, F, Niemeyer, C M, Trompouki, E, Wlodarski, M W & European Working Group of MDS in Childhood (EWOG-MDS) 2020, ' Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency ', Leukemia, vol. 34, no. 10, pp. 2673-2687 . https://doi.org/10.1038/s41375-020-0899-5 LEUKEMIA |
ISSN: | 1476-5551 0887-6924 |
Popis: | 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. |
Databáze: | OpenAIRE |
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