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
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
Externí odkaz: