Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
Genet Med. 2023 Sep;25(9):100900. doi: 10.1016/j.gim.2023.100900. Epub 2023 May 21.
5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive.
We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene.
We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment.
Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.
5-甲基胞嘧啶 RNA 修饰由 NSUN 甲基转移酶驱动。虽然 NSUN2 和 NSUN3 的变体与神经发育疾病有关，但 NSUN6 修饰对转移 RNA 和信使 RNA 的生理作用仍不清楚。
我们将同系亲属家系的外显子组测序与功能特征相结合，以鉴定新的神经发育障碍基因。
我们鉴定了 3 个无关的同系亲属家系，这些家系存在 NSUN6 有害纯合变异。其中两种变体被预测为失活功能。一种位于第一个外显子，预计通过无意义介导的衰变导致 NSUN6 缺失，而我们表明另一种位于最后一个外显子，编码不能正确折叠的蛋白质。同样，我们证明了在第三个家系中发现的错义变体已经失去了其酶活性，并且无法结合甲基供体 S-腺苷-L-甲硫氨酸。受影响的个体表现出发育迟缓、智力残疾、运动迟缓和行为异常。果蝇中 NSUN6 同源物的纯合缺失导致运动和学习障碍。
我们的数据提供了证据表明 NSUN6 的双等位基因致病性变异导致一种常染色体隐性智力残疾，这在 RNA 修饰和认知之间建立了另一个联系。
