De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity

• Published in: Scientific reports Vol. 7; no. 1; pp. 2887 - 8
• Main Authors: Nishi, Akira, Numata, Shusuke, Tajima, Atsushi, Zhu, Xiaolei, Ito, Koki, Saito, Atsushi, Kato, Yusuke, Kinoshita, Makoto, Shimodera, Shinji, Ono, Shinji, Ochi, Shinichiro, Imamura, Akira, Kurotaki, Naohiro, Ueno, Shu-Ichi, Iwata, Nakao, Fukui, Kiyoshi, Imoto, Issei, Kamiya, Atsushi, Ohmori, Tetsuro
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 06.06.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alleles; Amino Acid Substitution; Autism; Epilepsy; Exome; Exome Sequencing; Gene regulation; Genetic Predisposition to Disease; Humans; Mental disorders; Models, Molecular; Mutation; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Point mutation; Polymorphism, Single Nucleotide; Protein Conformation; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; Schizophrenia; Schizophrenia - genetics; Transcription; Wnt protein; Wnt Signaling Pathway; β-catenin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02792-z

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.