Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood
Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood
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DOI：
10.1016/j.ajhg.2017.07.002
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发表时间：
2017-08-03
影响因子：
9.8
通讯作者：
Elpeleg, Orly
中科院分区：
文献类型：
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作者：
Edvardson, Simon;Nicolae, Claudia M.;Elpeleg, Orly
核糖体 RNA (rRNA) 通过 RNA 聚合酶 I (Pol I) 从 rDNA 转录，产生核糖体的 28S、5.8S 和 18S rRNA 成分的 45S 前体。在哺乳动物中，已为 Pol I 定义了两个转录因子，即选择性因子 SL1 和上游结合转录因子 (UBF)，后者与上游控制元件相互作用，以促进包括 SL1 和 Pol I 在内的转录起始复合物的组装。在 7 个不相关的受影响个体中，所有个体均在 2.5-7 岁时开始发育退化，我们在 UBTF 中鉴定了一个杂合变体，c.628G>A，编码 p.Glu210Lys UBF，在所有情况下都是从头发生的。虽然受影响个体的细胞中 UBF、Ser388 磷酸化 UBF 和其他 Pol I 相关成分（POLR1E、TAF1A 和 TAF1C）的水平保持不变，但该变体赋予 UBF 功能增益，表现为 UBF 与 rDNA 启动子和 50 外部转录间隔区的结合显着增加。这与 18S 表达显着增加和核仁增大（每个细胞数量减少）有关。这些数据将儿童时期的神经退行性疾病与 rDNA 染色质状态和 rRNA 代谢的改变联系起来。
Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 50-external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.