CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.
CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.
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DOI：
10.1016/j.ajhg.2017.01.033
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发表时间：
2017-03-02
影响因子：
9.8
通讯作者：
Pearson CE
中科院分区：
文献类型：
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作者：
Barbé L;Lanni S;López-Castel A;Franck S;Spits C;Keymolen K;Seneca S;Tomé S;Miron I;Letourneau J;Liang M;Choufani S;Weksberg R;Wilson MD;Sedlacek Z;Gagnon C;Musova Z;Chitayat D;Shannon P;Mathieu J;Sermon K;Pearson CE
DMPK中的CTG重复扩增导致强直性肌营养不良（DM 1），其严重程度和发病年龄是连续的。先天性DM 1（CDM 1）是最严重的形式，具有独特的临床特征，大范围的扩展，几乎完全通过母体传播。CDM 1和扩张规模之间的相关性不是绝对的，表明其他因素的贡献。我们确定了20个受CDM 1影响的个体的79个血液样本中CTG重复序列侧翼的CpG甲基化; 21、27和11个具有母亲、父亲和未知遗传的DM 1但不具有CDM 1（此后为非CDM 1）的个体;以及母亲和父亲来源的绒毛膜绒毛样本（7个CVS）和人胚胎干细胞（4个hESC）的集合。除了两个受CDM 1影响的个体外，所有受CDM 1影响的个体在重复序列的上游和下游都显示出高水平的甲基化，高于非CDM 1个体（p = 7.04958 × 10−12）。大多数非CDM 1个体没有甲基化，其中六分之一显示下游甲基化。只有两个非CDM 1个体显示了上游甲基化，并且这些是母亲衍生的儿童期发病，表明甲基化随着发病年龄的连续性。只有母体来源的hESC和CVS显示上游甲基化。相比之下，父系来源的样品（27个血液样品，3个CVS和2个hESC）从未显示上游甲基化。CTG束长度与CDM 1或甲基化没有严格相关性。因此，CTG重复序列侧翼的甲基化模式是比重复序列大小更强的CDM 1指示剂。上游甲基化的精原细胞可能由于甲基化诱导的邻近SIX 5表达减少而无法存活，从而保护DM 1受影响的父亲不生CDM 1受影响的孩子。因此，DMPK甲基化可以解释母亲对CDM 1传播的偏好、较大的母亲CTG扩增、发病年龄和临床连续性，并且可以作为诊断指标。
CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10−12). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.