Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance
Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance
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DOI：
10.1186/s13148-020-00925-2
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发表时间：
2020-09-14
影响因子：
5.7
通讯作者：
Riccio, Andrea
中科院分区：
文献类型：
--
作者：
Cubellis, Maria Vittoria;Pignata, Laura;Riccio, Andrea
背景PADI 6是皮质下母体复合体的一个组成部分，是一组在卵母细胞胞质中大量表达的蛋白质，但对于早期胚胎的正确发育是必需的。皮质下母体复合物蛋白的母体效应变体与异质性疾病相关，包括女性不孕症、葡萄胎和多位点印迹障碍的印迹障碍。虽然PADI 6在不孕症中的作用已得到充分证实，但其在印迹疾病中的作用还不太明确。结果通过全外显子组测序分析，我们确定了4例Beckwith-Wiedemann综合征多位点印迹障碍患者，其母亲均为PADI 6变异携带者。计算机模拟分析表明，这些变异导致功能丧失，分离分析表明它们作为隐性或显性阴性母体效应突变。全基因组甲基化分析揭示了患者印迹基因座的异质性和广泛改变的甲基化谱，包括两个受影响的姐妹篇，但不是在他们的健康兄弟姐妹。结论PADI 6在印迹障碍中的作用得到了证实。我们报告的功能丧失的母体效应的变体ofPADI 6与异质性多位点印迹干扰的后代。两个兄弟姐妹受Beckwith-Wiedemann综合征影响的罕见发现表明，在某些情况下，这些变异的家族复发风险可能很高。然而，其他家系的异质性表型表明，卵母细胞PADI 6功能的改变导致甲基化印迹的随机维持，对早期胚胎健康产生不可预测的后果。
Background PADI6 is a component of the subcortical maternal complex, a group of proteins that is abundantly expressed in the oocyte cytoplasm, but is required for the correct development of early embryo. Maternal-effect variants of the subcortical maternal complex proteins are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders with multi-locus imprinting disturbance. While the involvement ofPADI6in infertility is well demonstrated, its role in imprinting disorders is less well established. Results We have identified by whole-exome sequencing analysis four cases of Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance whose mothers are carriers ofPADI6variants. In silico analysis indicates that these variants result in loss of function, and segregation analysis suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation analysis revealed heterogeneous and extensively altered methylation profiles of imprinted loci in the patients, including two affected sisters, but not in their healthy siblings. Conclusion Our results firmly establish the role ofPADI6in imprinting disorders. We report loss-of-function maternal-effect variants ofPADI6that are associated with heterogeneous multi-locus imprinting disturbances in the progeny. The rare finding of two siblings affected by Beckwith-Wiedemann syndrome suggests that in some cases, familial recurrence risk of these variants may be high. However, the heterogeneous phenotypes of the other pedigrees suggest that altered oocytePADI6function results in stochastic maintenance of methylation imprinting with unpredictable consequences on early embryo health.