Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency.
Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency.
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DOI：
10.1038/s41375-020-0899-5
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发表时间：
2020-10
期刊：
影响因子：
11.4
通讯作者：
European Working Group of MDS in Childhood (EWOG-MDS)
中科院分区：
文献类型：
--
作者：
Kozyra EJ;Pastor VB;Lefkopoulos S;Sahoo SS;Busch H;Voss RK;Erlacher M;Lebrecht D;Szvetnik EA;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 CM;Trompouki E;Wlodarski MW;European Working Group of MDS in Childhood (EWOG-MDS)
转录因子GATA 2的缺乏是一种高度渗透的遗传性疾病，易诱发骨髓增生异常综合征（MDS）和免疫缺陷。它被认为是儿童原发性MDS的最常见原因。触发发现一个经常性的同义GATA 2变异，我们系统地调查了911例表型的儿童MDS或细胞缺陷的GATA 2同义改变的存在。总共，我们鉴定了9个具有5个杂合同义突变的个体：c.351C>G，p.T117T（N = 4）; c.649C>T，p.L217L; c.981G>A，p.G327G; c.1023C>T，p.A341A;和c.1416G>A，p.P472P（N = 2）。在我们的队列中，它们占GATA 2缺陷病例的8.2%（9/110），并导致突变RNA的选择性丢失。虽然对于热点突变（c.351C>G），鉴定了导致RNA和蛋白质减少的剪接错误，但是对于其他突变，发现了严重的、可能的晚期RNA丢失而没有剪接破坏。最后，同义突变没有改变蛋白质的功能或稳定性。总之，同义GATA 2替换是GATA 2缺陷的新的常见原因。这些发现对孟德尔遗传病的遗传咨询和致病性变异的发现具有广泛的意义。
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.
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影响因子：
17.1
作者：
Cummings BB;Marshall JL;Tukiainen T;Lek M;Donkervoort S;Foley AR;Bolduc V;Waddell LB;Sandaradura SA;O'Grady GL;Estrella E;Reddy HM;Zhao F;Weisburd B;Karczewski KJ;O'Donnell-Luria AH;Birnbaum D;Sarkozy A;Hu Y;Gonorazky H;Claeys K;Joshi H;Bournazos A;Oates EC;Ghaoui R;Davis MR;Laing NG;Topf A;Genotype-Tissue Expression Consortium;Kang PB;Beggs AH;North KN;Straub V;Dowling JJ;Muntoni F;Clarke NF;Cooper ST;Bönnemann CG;MacArthur DG
通讯作者：
MacArthur DG
影响因子：
2
作者：
Macaya, D.;Katsanis, S. H.;Cutting, G. R.
通讯作者：
Cutting, G. R.
影响因子：
15.3
作者：
Abdulhay, Nour J.;Fiorini, Claudia;Sankaran, Vijay G.
通讯作者：
Sankaran, Vijay G.
DOI：
10.1172/jci91913
发表时间：
2017-05-01
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Buonocore F;Kühnen P;Suntharalingham JP;Del Valle I;Digweed M;Stachelscheid H;Khajavi N;Didi M;Brady AF;Blankenstein O;Procter AM;Dimitri P;Wales JKH;Ghirri P;Knöbl D;Strahm B;Erlacher M;Wlodarski MW;Chen W;Kokai GK;Anderson G;Morrogh D;Moulding DA;McKee SA;Niemeyer CM;Grüters A;Achermann JC
通讯作者：
Achermann JC
影响因子：
50.3
作者：
Goardon, Nicolas;Marchi, Emanuele;Vyas, Paresh
通讯作者：
Vyas, Paresh