The Mendelian disorders of the epigenetic machinery.
The Mendelian disorders of the epigenetic machinery.
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DOI：
10.1101/gr.190629.115
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发表时间：
2015-10
期刊：
影响因子：
7
通讯作者：
Bjornsson HT
中科院分区：
文献类型：
--
作者：
Bjornsson HT
表观遗传机制的孟德尔紊乱是涉及表观遗传机制各个组成部分（写入器、擦除器、读取器和重塑器）破坏的遗传性疾病，因此预计会产生广泛的下游表观遗传后果。研究这个群体可能提供一个独特的机会来了解表观遗传学在健康和疾病中的作用。在这些患者中，神经功能障碍，特别是智力障碍似乎是常见的表型；然而，这通常与相应疾病的其他更具体的特征相关。一些临床特征的特异性提出了一个问题：特定细胞类型是否对这些因子的丧失特别敏感。大多数这些疾病表现出剂量敏感性，因为单个等位基因的丢失似乎足以引起观察到的表型。尽管大多数这些疾病的致病序列尚不清楚，但有几个例子表明下游靶基因的表达破坏占表型的很大一部分；因此，系统地绘制这些与疾病相关的靶基因可能是有用的。最后，其中两种疾病（鲁宾斯坦-泰比综合征和歌舞伎综合征）已显示出产后可通过抑制组蛋白脱乙酰酶的药物来挽救神经功能障碍的标志物，这表明其中一些疾病可能是智力障碍的可治疗原因。
The Mendelian disorders of the epigenetic machinery are genetic disorders that involve disruption of the various components of the epigenetic machinery (writers, erasers, readers, and remodelers) and are thus expected to have widespread downstream epigenetic consequences. Studying this group may offer a unique opportunity to learn about the role of epigenetics in health and disease. Among these patients, neurological dysfunction and, in particular, intellectual disability appears to be a common phenotype; however, this is often seen in association with other more specific features in respective disorders. The specificity of some of the clinical features raises the question whether specific cell types are particularly sensitive to the loss of these factors. Most of these disorders demonstrate dosage sensitivity as loss of a single allele appears to be sufficient to cause the observed phenotypes. Although the pathogenic sequence is unknown for most of these disorders, there are several examples where disrupted expression of downstream target genes accounts for a substantial portion of the phenotype; hence, it may be useful to systematically map such disease-relevant target genes. Finally, two of these disorders (Rubinstein-Taybi and Kabuki syndromes) have shown post-natal rescue of markers of the neurological dysfunction with drugs that lead to histone deacetylase inhibition, indicating that some of these disorders may be treatable causes of intellectual disability.