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

European Working Group of MDS in Childhood (EWOG-MDS)

doi:10.1038/s41375-020-0899-5

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

European Working Group of MDS in Childhood (EWOG-MDS)

Institut für Experimentelle Dermatologie

Albert-Ludwigs-Universität Freiburg
Max-Planck-Institut für Immunbiologie und Epigenetik
St. Jude Children Research Hospital
Deutsches Krebsforschungszentrum
Hokkaido University Graduate School of Medicine
Vilnius University
IRCCS Ospedale pediatrico Bambino Gesù - Roma
Medizinische Hochschule Hannover
Hospital Sant Joan de Déu
Aarhus University
Princess Máxima Centre
Central Hospital of Southern Pest
University of Bologna
Ghent University
University of Vienna
Universität Zürich
Our Lady's Hospital for Sick Children
Charles University
Wroclaw Medical University
University College London
Royal Free London NHS Foundation Trust
Newcastle upon Tyne Hospitals NHS Foundation Trust
La Sapienza University of Rome

50 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Leukemia
Jahrgang	34
Ausgabenummer	10
Seiten (von - bis)	2673-2687
Seitenumfang	15
ISSN	0887-6924
DOIs	https://doi.org/10.1038/s41375-020-0899-5
Publikationsstatus	Veröffentlicht - 01.10.2020

Fördermittel

Acknowledgements This work was supported by grants from Fritz Thyssen Foundation 10.17.1.026MN (to MWW and ET); Deutsche Kinderkrebsstiftung DKS 2017.03, ERAPerMed by German Federal Ministry of Education and Research (BMBF) 2018-123/01KU1904, and Deutsche Krebshilfe 109005 (to MWW); José Carreras Leukemia Foundation (to VBP); Deutsche Forschungsgemeinschaft (DFG) 322977937/GRK2344 “MeInBio–BioInMe” (to ET and MB); Marie Curie Career Integration 631432 “Bloody Signals”, and DFG CIBSS-EXC-2189 390939984 (to ET), Baden-Württemberg LGFG stipend (to EJK), DFG EXC 22167-390884018 (to HB) and CRC850 (to MB), BMBF CoNfirm 01ZX1708F (to MB), and BMBF MyPred Network for young individuals with syndromes predisposing to myeloid malignancies (to MWW, ME, GG, CF, BS, and CMN). We are very grateful to Ayami-Yoshimi Nöllke, Lheanna Klaeyle, Sophie Krüger, Sandra Zolles, Christina Jäger, Sophia Hollander, Marco Teller, Ali-Riza Kaya, Alexandra Fischer, Wilfried Truckenmüller, Peter Nöllke, and Anne Strauss (Freiburg) for excellent assistance in diagnostic workup, laboratory work, and data management, and Prof. Dr. Rudolf Grosschedl (Max Planck Institute Freiburg), Dr. Claudia Wehr, and Dr. Ulrich Salzer (Freiburg) for helpful discussions. The authors also thank all members of the European Working Group of MDS in Childhood (EWOG-MDS) for performing reference examinations (pathology, cytogenetics, molecular genetics), HSCT or other forms of patient care. This work was performed within the European Reference Network for Paediatric Cancer (ERN-PAEDCAN). The authors acknowledge the contribution of the Center of Inborn and Acquired Blood Diseases at the Freiburg Center for Rare Diseases, and the Hilda Biobank at the Department of Pediatrics and Adolescent Medicine, Freiburg, Germany.

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen
SDG 9 – Industrie, Innovation und Infrastruktur

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

DFG-Fachsystematik

2.21-05 Immunologie

Zugriff auf Dokument

10.1038/s41375-020-0899-5

Andere Dateien und Links

Link to publication in Scopus

Dieses zitieren

@article{fa82323149b84fd7986afc836db21c06,

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

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.",

author = "\{European Working Group of MDS in Childhood (EWOG-MDS)\} and Kozyra, \{Emilia J.\} and Pastor, \{Victor B.\} and Stylianos Lefkopoulos and Sahoo, \{Sushree S.\} and Hauke Busch and Voss, \{Rebecca K.\} and Miriam Erlacher and Dirk Lebrecht and Szvetnik, \{Enikoe A.\} and Shinsuke Hirabayashi and Ramunė Pasaulienė and Lucia Pedace and Marco Tartaglia and Christian Klemann and Patrick Metzger and Melanie Boerries and Albert Catala and Henrik Hasle and \{de Haas\}, Valerie and Kriszti{\'a}n K{\'a}llay and Riccardo Masetti and \{De Moerloose\}, Barbara and Michael Dworzak and Markus Schmugge and Owen Smith and Jan Star{\'y} and Ester Mejstrikova and Marek Ussowicz and Emma Morris and Preeti Singh and Matthew Collin and Marta Derecka and Gudrun G{\"o}hring and Christian Flotho and Brigitte Strahm and Franco Locatelli and Niemeyer, \{Charlotte M.\} and Eirini Trompouki and Wlodarski, \{Marcin W.\}",

year = "2020",

month = oct,

day = "1",

doi = "10.1038/s41375-020-0899-5",

language = "English",

volume = "34",

pages = "2673--2687",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

number = "10",

}

TY - JOUR

T1 - Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency

AU - European Working Group of MDS in Childhood (EWOG-MDS)

AU - Kozyra, Emilia J.

AU - Pastor, Victor B.

AU - Lefkopoulos, Stylianos

AU - Sahoo, Sushree S.

AU - Busch, Hauke

AU - Voss, Rebecca K.

AU - Erlacher, Miriam

AU - Lebrecht, Dirk

AU - Szvetnik, Enikoe A.

AU - Hirabayashi, Shinsuke

AU - Pasaulienė, Ramunė

AU - Pedace, Lucia

AU - Tartaglia, Marco

AU - Klemann, Christian

AU - Metzger, Patrick

AU - Boerries, Melanie

AU - Catala, Albert

AU - Hasle, Henrik

AU - de Haas, Valerie

AU - Kállay, Krisztián

AU - Masetti, Riccardo

AU - De Moerloose, Barbara

AU - Dworzak, Michael

AU - Schmugge, Markus

AU - Smith, Owen

AU - Starý, Jan

AU - Mejstrikova, Ester

AU - Ussowicz, Marek

AU - Morris, Emma

AU - Singh, Preeti

AU - Collin, Matthew

AU - Derecka, Marta

AU - Göhring, Gudrun

AU - Flotho, Christian

AU - Strahm, Brigitte

AU - Locatelli, Franco

AU - Niemeyer, Charlotte M.

AU - Trompouki, Eirini

AU - Wlodarski, Marcin W.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85086588426

U2 - 10.1038/s41375-020-0899-5

DO - 10.1038/s41375-020-0899-5

M3 - Journal articles

C2 - 32555368

AN - SCOPUS:85086588426

SN - 0887-6924

VL - 34

SP - 2673

EP - 2687

JO - Leukemia

JF - Leukemia

IS - 10

ER -

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

Abstract

Fördermittel

UN SDGs

Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

Zugriff auf Dokument

Andere Dateien und Links

Fingerprint

Dieses zitieren