ZNF445: a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance.
ZNF445: a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance.
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DOI：
10.1186/s13148-021-01106-5
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发表时间：
2021-05-26
影响因子：
5.7
通讯作者：
Ogata T
中科院分区：
文献类型：
--
作者：
Kagami M;Hara-Isono K;Matsubara K;Nakabayashi K;Narumi S;Fukami M;Ohkubo Y;Saitsu H;Takada S;Ogata T
ZNF 445和ZFP 57一样，参与受精后多个印记相关差异甲基化区域（iDMR）的甲基化维持。因此，预测ZNF 445致病性变体会引起多位点印迹干扰（MLID），ZFP 57致病性变体也是如此。特别是MEG 3/DLK 1：IG-DMR会受到影响，因为MEG 3/DLK 1：IG-DMR的合子后甲基化印记主要由ZNF 445维持，而大多数iDMR的合子后甲基化印记由ZFP 57和ZNF 445或主要由ZFP 57维持。我们在6名患有由表位突变引起的各种印记疾病（ID）的患者中搜索ZNF 445变体，并通过焦磷酸测序对9个iDMR进行了MLID，而没有选择原始ID。对先前获得的全外显子组测序数据的再分析鉴定了纯合ZNF 445变体（NM_181489.（Gln 935 *）），其在患有Temple综合征和MLID的患者中产生缺失14个锌指结构域中的两个的截短蛋白。在该患者中，基于阵列的全基因组甲基化分析显示，MEG 3：TSS-DMR处的大多数CpG存在重度低甲基化，H19/IGF 2：IG-DMR处约三分之二的CpG存在中度低甲基化，DIRAS 3：TSS-DMR、MEST：alt-TSS-DMR、IGF 2：Ex 9-DMR、IGF 2：alt-TSS和GNAS-AS 1：TSS-DMR处的少数CpG存在轻度至中度低甲基化。此外，MEG 3/DLK 1：IG-DMR的亚硫酸氢盐测序分析描绘了显著低甲基化片段（CG-A）。杂合子父母临床正常，几乎没有异常甲基化模式。我们首次鉴定了ZNF 445致病性变体。由于ZNF 445与MEG 3/DLK 1：IG-DMR和该患者受影响的其他iDMR结合，因此Temple综合征和MLID的发生主要由ZNF 445变体解释。此外，CG-A可能是MEG 3/DLK 1：IG-DMR中ZNF 445的靶位点。在线版本包含补充材料，可通过10.1186/s13148-021-01106-5获得。
ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57. We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern. We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR. The online version contains supplementary material available at 10.1186/s13148-021-01106-5.
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全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
影响因子：
4.4
作者：
Nord AS;Lee M;King MC;Walsh T
通讯作者：
Walsh T
影响因子：
3.8
作者：
Bens, Susanne;Kolarova, Julia;Siebert, Reiner
通讯作者：
Siebert, Reiner
影响因子：
5.7
作者：
Cubellis, Maria Vittoria;Pignata, Laura;Riccio, Andrea
通讯作者：
Riccio, Andrea
DOI：
10.1038/gim.2017.53
发表时间：
2017-12
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Kagami M;Nagasaki K;Kosaki R;Horikawa R;Naiki Y;Saitoh S;Tajima T;Yorifuji T;Numakura C;Mizuno S;Nakamura A;Matsubara K;Fukami M;Ogata T
通讯作者：
Ogata T