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

Adolescent Adult Child Child, Preschool Female GATA2 Deficiency / genetics GATA2 Transcription Factor / deficiency Genetic Association Studies Genetic Predisposition to Disease / genetics Germ-Line Mutation / genetics Heterozygote Humans Immunologic Deficiency Syndromes / genetics Male Myelodysplastic Syndromes / genetics Phenotype RNA / genetics Silent Mutation / genetics Young Adult

Journal

Leukemia

ISSN: 1476-5551

Titre abrégé: Leukemia

Pays: England

ID NLM: 8704895

Informations de publication

Date de publication:
10 2020

Historique:

received: 18 09 2019

accepted: 29 05 2020

revised: 19 05 2020

pubmed: 20 6 2020

medline: 21 11 2020

entrez: 20 6 2020

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41375-020-0899-5 PMID: 32555368 PMC: PMC7515837

pubmed: 32555368

doi: 10.1038/s41375-020-0899-5

pii: 10.1038/s41375-020-0899-5

pmc: PMC7515837

doi:

Substances chimiques

GATA2 Transcription Factor 0

GATA2 protein, human 0

RNA 63231-63-0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

2673-2687

Subventions

Organisme : Medical Research Council

ID : MR/P002005/1

Pays : United Kingdom

Références

Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 2011;118:2653–5.

pubmed: 21670465 pmcid: 3172785 doi: 10.1182/blood-2011-05-356352

Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011;118:2656–8.

pubmed: 21765025 doi: 10.1182/blood-2011-06-360313

Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43:1012–7.

pubmed: 21892162 pmcid: 3184204 doi: 10.1038/ng.913

Pasquet M, Bellanne-Chantelot C, Tavitian S, Prade N, Beaupain B, Larochelle O, et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood. 2013;121:822–9.

pubmed: 23223431 pmcid: 3714670 doi: 10.1182/blood-2012-08-447367

Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011;43:929–31.

pubmed: 21892158 doi: 10.1038/ng.923

Dorn JM, Patnaik MS, Van Hee M, Smith MJ, Lagerstedt SA, Newman CC, et al. WILD syndrome is GATA2 deficiency: a novel deletion in the GATA2 gene. J Allergy Clin Immunol Pract. 2017;5:1149–52.

pubmed: 28373026 doi: 10.1016/j.jaip.2017.02.010

Wlodarski MW, Hirabayashi S, Pastor V, Stary J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 2016;127:1387–97.

doi: 10.1182/blood-2015-09-669937 pubmed: 26702063

Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM. Heterogeneity of GATA2-related myeloid neoplasms. Int J Hematol. 2017;106:175–82.

pubmed: 28643018 doi: 10.1007/s12185-017-2285-2

Wlodarski M, Collin M, Horwitz MS. GATA2 deficiency and related myeloid neoplasms. Seminars in Hematology. 2017;54:81–6.

pubmed: 28637621 pmcid: 5650112 doi: 10.1053/j.seminhematol.2017.05.002

Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD, et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood 2013;121:3830–7. S1-7

pubmed: 23502222 pmcid: 3650705 doi: 10.1182/blood-2012-08-452763

Hahn CN, Brautigan PJ, Chong CE, Janssan A, Venugopal P, Lee Y, et al. Characterisation of a compound in-cis GATA2 germline mutation in a pedigree presenting with myelodysplastic syndrome/acute myeloid leukemia with concurrent thrombocytopenia. Leukemia 2015;29:1795–7.

pubmed: 25676417 doi: 10.1038/leu.2015.40

Cortes-Lavaud X, Landecho MF, Maicas M, Urquiza L, Merino J, Moreno-Miralles I, et al. GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation. J Immunol. 2015;194:2190–8.

pubmed: 25624456 doi: 10.4049/jimmunol.1401868

Sologuren I, Martinez-Saavedra MT, Sole-Violan J, de Borges de Oliveira E Jr, Betancor E, Casas I, et al. Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency. J Clin Immunol. 2018;38:513–26.

pubmed: 29882021 pmcid: 6429553 doi: 10.1007/s10875-018-0512-0

Chong CE, Venugopal P, Stokes PH, Lee YK, Brautigan PJ, Yeung DTO, et al. Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes. Leukemia 2018;32:194–202.

pubmed: 28642594 doi: 10.1038/leu.2017.196

D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, et al. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci USA. 1999;96:5598–603.

pubmed: 10318930 doi: 10.1073/pnas.96.10.5598 pmcid: 21906

Cartegni L, Krainer AR. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat Genet 2002;30:377–84.

pubmed: 11925564 doi: 10.1038/ng854

Macaya D, Katsanis SH, Hefferon TW, Audlin S, Mendelsohn NJ, Roggenbuck J, et al. A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon. Am J Med Genet A 2009;149A:1624–7.

pubmed: 19572402 doi: 10.1002/ajmg.a.32834

Vidal C, Cachia A, Xuereb-Anastasi A. Effects of a synonymous variant in exon 9 of the CD44 gene on pre-mRNA splicing in a family with osteoporosis. Bone 2009;45:736–42.

pubmed: 19580891 doi: 10.1016/j.bone.2009.06.027

Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet. 2003;12:205–16.

pubmed: 12554675 doi: 10.1093/hmg/ddg055

Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 2005;15:693–704.

pubmed: 16141795 doi: 10.1097/01.fpc.0000178311.02878.83

Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 2006;314:1930–3.

pubmed: 17185601 doi: 10.1126/science.1131262

Buhr F, Jha S, Thommen M, Mittelstaet J, Kutz F, Schwalbe H, et al. Synonymous Codons Direct Cotranslational Folding toward Different Protein Conformations. Mol cell 2016;61:341–51.

pubmed: 26849192 pmcid: 4745992 doi: 10.1016/j.molcel.2016.01.008

Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet 2011;43:242–5.

pubmed: 21278745 doi: 10.1038/ng.762

Simhadri VL, Hamasaki-Katagiri N, Lin BC, Hunt R, Jha S, Tseng SC, et al. Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B. J Med Genet. 2017;54:338–45.

pubmed: 28007939 doi: 10.1136/jmedgenet-2016-104072

Wehr C, Grotius K, Casadei S, Bleckmann D, Bode SFN, Frye BC, et al. A novel disease-causing synonymous exonic mutation in GATA2 affecting RNA splicing. Blood 2018;132:1211–5.

pubmed: 30030275 pmcid: 6137559 doi: 10.1182/blood-2018-03-837336

Baumann I, Niemeyer CMBJ, Shannon K WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008. p. 104–7.

Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009;114:937–51.

pubmed: 19357394 doi: 10.1182/blood-2009-03-209262

Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391–405.

doi: 10.1182/blood-2016-03-643544 pubmed: 27069254

Pastor V, Hirabayashi S, Karow A, Wehrle J, Kozyra EJ, Nienhold R, et al. Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia. 2016;31:759–62.

pubmed: 27876779 doi: 10.1038/leu.2016.342

Bluteau O, Sebert M, Leblanc T, Peffault de Latour R, Quentin S, Lainey E, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 2018;131:717–32.

pubmed: 29146883 doi: 10.1182/blood-2017-09-806489

Buonocore F, Kuhnen P, Suntharalingham JP, Del Valle I, Digweed M, Stachelscheid H, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest. 2017;127:1700–13.

pubmed: 28346228 pmcid: 5409795 doi: 10.1172/JCI91913

Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet 2016;48:792–7.

pubmed: 27182967 doi: 10.1038/ng.3569

Huang Z, Dore LC, Li Z, Orkin SH, Feng G, Lin S, et al. GATA-2 reinforces megakaryocyte development in the absence of GATA-1. Mol Cell Biol. 2009;29:5168–80.

pubmed: 19620289 pmcid: 2738300 doi: 10.1128/MCB.00482-09

Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S, et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 2011;19:138–52.

pubmed: 21251617 doi: 10.1016/j.ccr.2010.12.012

Butko E, Distel M, Pouget C, Weijts B, Kobayashi I, Ng K, et al. Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo. Development 2015;142:1050–61.

pubmed: 25758220 pmcid: 4360177 doi: 10.1242/dev.119180

Schwartz JR, Wang S, Ma J, Lamprecht T, Walsh M, Song G, et al. Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome. Leukemia 2017;31:1827–30.

pubmed: 28487541 pmcid: 5540771 doi: 10.1038/leu.2017.142

Novakova M, Zaliova M, Sukova M, Wlodarski M, Janda A, Fronkova E, et al. Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome. Haematologica 2016;101:707–16.

pubmed: 27013649 pmcid: 5013954 doi: 10.3324/haematol.2015.137711

Abdulhay NJ, Fiorini C, Verboon JM, Ludwig LS, Ulirsch JC, Zieger B, et al. Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation. J Exp Med. 2019;216:1050–60.

pubmed: 30914438 pmcid: 6504223 doi: 10.1084/jem.20181625

Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Rodger E, Kelley ML, et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol. 2015;22:3–11.

pubmed: 25427142 pmcid: 4380169 doi: 10.1097/MOH.0000000000000105

Supek F, Minana B, Valcarcel J, Gabaldon T, Lehner B. Synonymous mutations frequently act as driver mutations in human cancers. Cell 2014;156:1324–35.

pubmed: 24630730 doi: 10.1016/j.cell.2014.01.051

Pirinen M, Lappalainen T, Zaitlen NA, Consortium GT, Dermitzakis ET, Donnelly P, et al. Assessing allele-specific expression across multiple tissues from RNA-seq read data. Bioinformatics 2015;31:2497–504.

pubmed: 25819081 pmcid: 4514921 doi: 10.1093/bioinformatics/btv074

Wilkins JM, Southam L, Price AJ, Mustafa Z, Carr A, Loughlin J. Extreme context specificity in differential allelic expression. Hum Mol Genet. 2007;16:537–46.

pubmed: 17220169 doi: 10.1093/hmg/ddl488

Serre D, Gurd S, Ge B, Sladek R, Sinnett D, Harmsen E, et al. Differential allelic expression in the human genome: a robust approach to identify genetic and epigenetic cis-acting mechanisms regulating gene expression. PLoS Genet 2008;4:e1000006.

pubmed: 18454203 pmcid: 2265535 doi: 10.1371/journal.pgen.1000006

Al Seraihi AF, Rio-Machin A, Tawana K, Bodor C, Wang J, Nagano A, et al. GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2-mutated MDS/AML. Leukemia. 2018;32:2502–7.

pubmed: 29749400 pmcid: 6224398 doi: 10.1038/s41375-018-0134-9

Nandakumar SK, Johnson K, Throm SL, Pestina TI, Neale G, Persons DA. Low-level GATA2 overexpression promotes myeloid progenitor self-renewal and blocks lymphoid differentiation in mice. Exp Hematol 2015;43:565–77.e1-10.

pubmed: 25907033 doi: 10.1016/j.exphem.2015.04.002

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet 2015;47:717–26.

pubmed: 25985138 pmcid: 4601524 doi: 10.1038/ng.3304

Ji J, Shen L, Bootwalla M, Quindipan C, Tatarinova T, Maglinte DT, et al. A semi-automated whole exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. Cold Spring Harb Mol Case Stud. 2019;5:a003756.

pubmed: 30755392 pmcid: 6549575 doi: 10.1101/mcs.a003756

Cummings BB, Marshall JL, Tukiainen T, Lek M, Donkervoort S, Foley AR, et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med. 2017;9:eaal5209.

pubmed: 28424332 pmcid: 5548421 doi: 10.1126/scitranslmed.aal5209

Kremer LS, Bader DM, Mertes C, Kopajtich R, Pichler G, Iuso A, et al. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat Commun 2017;8:15824.

pubmed: 28604674 pmcid: 5499207 doi: 10.1038/ncomms15824