Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring.
Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring.
复制标题
DOI：
10.1136/jmedgenet-2017-105190
复制
发表时间：
2018-07
影响因子：
4
通讯作者：
Mackay DJG
中科院分区：
文献类型：
--
作者：
Begemann M;Rezwan FI;Beygo J;Docherty LE;Kolarova J;Schroeder C;Buiting K;Chokkalingam K;Degenhardt F;Wakeling EL;Kleinle S;González Fassrainer D;Oehl-Jaschkowitz B;Turner CLS;Patalan M;Gizewska M;Binder G;Bich Ngoc CT;Chi Dung V;Mehta SG;Baynam G;Hamilton-Shield JP;Aljareh S;Lokulo-Sodipe O;Horton R;Siebert R;Elbracht M;Temple IK;Eggermann T;Mackay DJG
基因组印记是少数哺乳动物基因在早期胚胎中抗重编程的种系表观遗传标记的结果。遗传、表观遗传或环境损害阻止印记逃避重编程，可能导致印记障碍，影响生长、发育、行为和代谢。我们的目的是通过对有一个或多个成员受到多位点印记障碍影响的家庭进行全外显子组测序来确定引起印记疾病的遗传缺陷。对38个先证有多位点印迹干扰的家系进行了全外显子组测序，其中5个家系中已有NLRP5的母系变异。我们现在报告了另外15个家系，其中后代有印迹障碍，而他们的母亲在母体效应基因中有罕见的、可预测的有害变异，包括NLRP2、NLRP7和PADI6。除了公认的印记障碍的临床特征外，一些后代还有其他特征，包括发育迟缓、行为问题和不一致的同卵双胞胎，而一些母亲有生殖问题，包括流产。在38个受多位点印记疾病影响的家庭中鉴定出20个假定的母体效应变异，进一步证明母体遗传因素影响卵母细胞适应性，从而影响后代的发育。在受非典型印记疾病影响的家庭中，应考虑检测母体影响的遗传变异。
Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance. Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found. We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.
登录
查看更多内容
体内和体外衰老会影响鼠卵母细胞中的成熟率，丰富的蛋白质，组蛋白甲基化模式和纺锤体完整性。
影响因子：
3.7
作者：
Demond H;Trapphoff T;Dankert D;Heiligentag M;Grümmer R;Horsthemke B;Eichenlaub-Ritter U
通讯作者：
Eichenlaub-Ritter U
影响因子：
4.6
作者：
Mahadevan S;Sathappan V;Utama B;Lorenzo I;Kaskar K;Van den Veyver IB
通讯作者：
Van den Veyver IB
影响因子：
5.8
作者：
Radian AD;de Almeida L;Dorfleutner A;Stehlik C
通讯作者：
Stehlik C
影响因子：
3.7
作者：
Kim B;Kan R;Anguish L;Nelson LM;Coonrod SA
通讯作者：
Coonrod SA
影响因子：
3.5
作者：
Begemann, M.;Spengler, S.;Eggermann, T.
通讯作者：
Eggermann, T.