De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity

Akira Nishi; Shusuke Numata; Atsushi Tajima; Xiaolei Zhu; Koki Ito; Atsushi Saito; Yusuke Kato; Makoto Kinoshita; Shinji Shimodera; Shinji Ono; Shinichiro Ochi; Akira Imamura; Naohiro Kurotaki; Shu Ichi Ueno; Nakao Iwata; Kiyoshi Fukui; Issei Imoto; Atsushi Kamiya; Tetsuro Ohmori

doi:10.1038/s41598-017-02792-z

De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity

Akira Nishi, Shusuke Numata, Atsushi Tajima, Xiaolei Zhu, Koki Ito, Atsushi Saito, Yusuke Kato, Makoto Kinoshita, Shinji Shimodera, Shinji Ono, Shinichiro Ochi, Akira Imamura, Naohiro Kurotaki, Shu Ichi Ueno, Nakao Iwata, Kiyoshi Fukui, Issei Imoto, Atsushi Kamiya, Tetsuro Ohmori

School of Medicine

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Abstract

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.

Original language	English (US)
Article number	2887
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-02792-z
State	Published - Dec 1 2017

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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, S. I., Iwata, N., Fukui, K., Imoto, I., Kamiya, A., & Ohmori, T. (2017). De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity. Scientific reports, 7(1), Article 2887. https://doi.org/10.1038/s41598-017-02792-z

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abstract = "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.",

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AU - Zhu, Xiaolei

AU - Ito, Koki

AU - Saito, Atsushi

AU - Kato, Yusuke

AU - Kinoshita, Makoto

AU - Shimodera, Shinji

AU - Ono, Shinji

AU - Ochi, Shinichiro

AU - Imamura, Akira

AU - Kurotaki, Naohiro

AU - Ueno, Shu Ichi

AU - Iwata, Nakao

AU - Fukui, Kiyoshi

AU - Imoto, Issei

AU - Kamiya, Atsushi

AU - Ohmori, Tetsuro

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De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity

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