Increased MTHFR promoter methylation in mothers of Down syndrome individuals
Increased MTHFR promoter methylation in mothers of Down syndrome individuals
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DOI：
10.1016/j.mrfmmm.2016.02.008
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发表时间：
2016-05-01
影响因子：
2.3
通讯作者：
Migliore, Lucia
中科院分区：
文献类型：
--
作者：
Coppede, Fabio;Denaro, Maria;Migliore, Lucia
尽管怀孕时的高龄产妇是出生唐氏综合征（DS）儿童的主要风险因素，但大多数DS婴儿都是由年龄小于35岁的女性出生的。在这些妇女的外周淋巴细胞中进行的研究揭示了全球基因组不稳定性的几个标志物，包括微核频率增加，端粒缩短和全球DNA甲基化受损。此外，年轻的母亲的DS个人（MDS）在以后的生活中发展为痴呆症的风险增加，这表明他们可能是“生物年龄”比母亲的整倍体婴儿的年龄相仿。叶酸途径基因的突变，特别是在亚甲基四氢叶酸还原酶（MTHFR）的一个，往往与母亲的风险DS出生以及老年痴呆症的风险。最近的研究指出，MTHFR甲基化水平的变化也可能导致人类疾病，但对MDS组织中的MTHFR甲基化一无所知。我们研究了从40名MDS和44名匹配的对照妇女的外周淋巴细胞提取的DNA中的MTHFR启动子甲基化，这些妇女在35岁之前生育了她们的孩子。在第一组中观察到显著增加的MTHFR启动子甲基化（33.3 +/- 8.1%对28.3 +/- 5.8%; p = 0.001）。此外，本研究中的妇女的微核淋巴细胞频率高于对照组母亲（16.1 +/- 8.6份/千份对10.5 +/- 4.3份/千份; p = 0.0004），并与MTHFR启动子甲基化水平相关（r = 0.33; p = 0.006）。目前的数据表明，MTHFR表突变可能有助于在来自MDS的细胞中观察到的增加的基因组不稳定性，并且可能在患有DS的儿童的出生风险中以及在那些妇女中年龄相关疾病的发作中起作用。(C)© 2016 Elsevier B. V.版权所有。
Despite that advanced maternal age at conception represents the major risk factor for the birth of a child with Down syndrome (DS), most of DS babies are born from women aging less than 35 years. Studies performed in peripheral lymphocytes of those women revealed several markers of global genome instability, including an increased frequency of micronuclei, shorter telomeres and impaired global DNA methylation. Furthermore, young mothers of DS individuals (MDS) are at increased risk to develop dementia later in life, suggesting that they might be "biologically older" than mothers of euploid babies of similar age.Mutations in folate pathway genes, and particularly in the methylenetetrahydrofolate reductase (MTHFR) one, have been often associated with maternal risk for a DS birth as well as with risk of dementia in the elderly. Recent studies pointed out that also changes in MTHFR methylation levels can contribute to human disease, but nothing is known about MTHFR methylation in MDS tissues.We investigated MTHFR promoter methylation in DNA extracted from perypheral lymphocytes of 40 MDS and 44 matched control women that coinceived their children before 35 years of age, observing a significantly increased MTHFR promoter methylation in the first group (33.3 +/- 8.1% vs. 28.3 +/- 5.8%; p = 0.001). In addition, the frequency of micronucleated lymphocytes was available from the women included in the study, was higher in MDS than control mothers (16.1 +/- 8.6 parts per thousand vs. 10.5 +/- 4.3 parts per thousand; p = 0.0004), and correlated with MTHFR promoter methylation levels (r = 0.33; p = 0.006).Present data suggest that MTHFR epimutations are likely to contribute to the increased genomic instability observed in cells from MDS, and could play a role in the risk of birth of a child with DS as well as in the onset of age related diseases in those women. (C) 2016 Elsevier B.V. All rights reserved.