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De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity.

Akira NishiShusuke NumataAtsushi TajimaXiaolei ZhuKoki ItoAtsushi SaitoYusuke KatoMakoto KinoshitaShinji ShimoderaShinji OnoShinichiro OchiAkira ImamuraNaohiro KurotakiShu-Ichi UenoNakao IwataKiyoshi FukuiIssei ImotoAtsushi KamiyaTetsuro Ohmori
Published in: Scientific reports (2017)
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.
Keyphrases
  • cell proliferation
  • stem cells
  • gene expression
  • copy number
  • bipolar disorder
  • oxidative stress
  • genome wide
  • epithelial mesenchymal transition
  • dna methylation
  • late onset
  • early onset
  • heat shock protein