CTNNA3 discordant regulation of nested LRRTM3, implications for autism spectrum disorder and Tourette syndrome

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• 关键词：Tourette Syndrome ; Autism ; NTSC ; Mutation hot spot ; Nested genes ; Transcriptional interference
• 刊名：Meta Gene
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：11
• 期：Complete
• 页码：43-48
• 全文大小：605 K
• 卷排序：11

文摘

Autism Spectrum Disorder (ASD) and Tourette syndrome (TS) are poorly understood neurodevelopment disorders with strong male bias, high heritability and complex genetic heterogeneity. IMMP2L and CTNNA3 are associated with ASD and TS and both harbour nested genes LRRN3 and LRRTM3, respectively, that demonstrate independent association with ASD. LRRTM3 encodes a trans-synaptic ligand for neurexin 1 (NRXN1). NRXN1 has been recurrently disrupted in ASD and TS suggesting that complex overlapping pathogenetic processes are at play in these two disorders.MethodsThe in vitro expression levels of the overlapping gene sets IMMP2L-LRRN3 and CTNNA3-LRRTM3 were quantified using comparative PCR (CTPCR) before and after targeting each of the harbouring genes with siRNA. An Immp2l-gene trap (Immp2lGT) mouse strain was developed to test expression effects on the nested lrrn3 gene.ResultsReduced expression levels of IMMP2L in vitro and of Immp2l in Immp2lGT mice had no observable effect on the expression level of their nested genes LRRN3 and lrrn3, respectively. In contrast, the siRNA mediated down regulation of CTNNA3 levels resulted in concurrent increases in the expression level of its nested gene LRRTM3.ConclusionThe discordant regulation of LRRTM3 by CTNNA3 may help explain its association with ASD and TS. LRRTM3 completes the set of neurexin trans-synaptic ligand gene families associated with ASD and TS reinforcing the status of the NTSC as a mutation hotspot for TS and a strong point of molecular overlap between TS and ASD.