De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity.
De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity.
复制标题
DOI：
10.1038/s41598-017-02792-z
复制
发表时间：
2017-06-06
影响因子：
4.6
通讯作者：
Ohmori T
中科院分区：
文献类型：
--
作者：
Nishi A;Numata S;Tajima A;Zhu X;Ito K;Saito A;Kato Y;Kinoshita M;Shimodera S;Ono S;Ochi S;Imamura A;Kurotaki N;Ueno SI;Iwata N;Fukui K;Imoto I;Kamiya A;Ohmori T
在这里，我们通过对日本散发性精神分裂症患者及其父母组成的18个三联体进行全外显子测序，报告了非同义单核苷酸变异(SNV)。在9个SNV中，我们探索了TBL1XR1[c.30 C >； G(p.Phe10Leu)]从头突变对功能的影响，该基因以前被发现与自闭症谱系障碍和癫痫有关。蛋白质结构分析表明，Phe10Leu突变可能降低了TBL1XR1蛋白的结构稳定性。我们证明，Phe10Leu突变改变了TbL1XR1与N-COR和β-连环蛋白的相互作用，这在调节WNT介导的转录活性中发挥了关键作用。一致地，TbL1XR1介导的Wnt信号的激活被Phe10Leu突变上调。这些结果表明，TbL1XR1点突变可以改变Wnt/β-catenin信号活性。需要进一步的研究来阐明TBL1XR1突变与神经精神疾病的关系。
Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [c.30 C > G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and β-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/β-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions.