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首页> 外文期刊>International Journal of Molecular Sciences >High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies
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High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies

机译：突触结合蛋白样蛋白4（SYTL4）和跨膜蛋白187（TMEM187）基因错义突变的高功能自闭症：SYTL4-蛋白建模，蛋白-蛋白质相互作用，表达谱分析和MicroRNA研究

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We describe a 7-year-old male with high functioning autism spectrum disorder (ASD) and maternally-inherited rare missense variant of Synaptotagmin-like protein 4 ( SYTL4) gene (Xq22.1; c.835CT; p.Arg279Cys) and an unknown missense variant of Transmembrane protein 187 ( TMEM187 ) gene (Xq28; c.708GT; p. Gln236His). Multiple in-silico predictions described in our study indicate a potentially damaging status for both X-linked genes. Analysis of predicted atomic threading models of the mutant and the native SYTL4 proteins suggest a potential structural change induced by the R279C variant which eliminates the stabilizing Arg279-Asp60 salt bridge in the N-terminal half of the SYTL4, affecting the functionality of the protein’s critical RAB-Binding Domain. In the European (Non-Finnish) population, the allele frequency for this variant is 0.00042. The SYTL4 gene is known to directly interact with several members of the RAB family of genes, such as, RAB27A, RAB27B, RAB8A, and RAB3A which are known autism spectrum disorder genes. The SYTL4 gene also directly interacts with three known autism genes: STX1A , SNAP25 and STXBP1. Through a literature-based analytical approach, we identified three of five (60%) autism-associated serum microRNAs (miRs) with high predictive power among the total of 298 mouse Sytl4 associated/predicted microRNA interactions. Five of 13 (38%) miRs were differentially expressed in serum from ASD individuals which were predicted to interact with the mouse equivalent Sytl 4 gene. TMEM187 gene, like SYTL4 , is a protein-coding gene that belongs to a group of genes which host microRNA genes in their introns or exons. The novel Q236H amino acid variant in the TMEM187 in our patient is near the terminal end region of the protein which is represented by multiple sequence alignments and hidden Markov models, preventing comparative structural analysis of the variant harboring region. Like SYTL4 , the TMEM187 gene is expressed in the brain and interacts with four known ASD genes, namely, HCFC1; TMLHE; MECP2 ; and GPHN. TMM187 is in linkage with MECP2 , which is a well-known determinant of brain structure and size and is a well-known autism gene. Other members of the TMEM gene family, TMEM132E and TMEM132D genes are associated with bipolar and panic disorders, respectively, while TMEM231 is a known syndromic autism gene. Together, TMEM187 and SYTL4 genes directly interact with recognized important ASD genes, and their mRNAs are found in extracellular vesicles in the nervous system and stimulate target cells to translate into active protein. Our evidence shows that both these genes should be considered as candidate genes for autism. Additional biological testing is warranted to further determine the pathogenicity of these gene variants in the causation of autism.
机译：我们描述了一个7岁的男性，患有高功能自闭症谱系障碍（ASD）和母本遗传的突触突触素样蛋白4（SYTL4）基因的稀有错义变体（Xq22.1; c.835C> T; p.Arg279Cys）以及未知的跨膜蛋白187（TMEM187）基因的错义变体（Xq28; c.708G> T; p。Gln236His）。我们研究中描述的多种计算机内预测表明，这两个X连锁基因均具有潜在的破坏状态。对突变体和天然SYTL4蛋白质的预测原子穿入模型的分析表明，R279C变异体诱导了潜在的结构变化，从而消除了SYTL4 N端一半的稳定Arg279-Asp60盐桥，影响了蛋白质关键分子的功能。 RAB绑定域。在欧洲（非芬兰）人群中，此变体的等位基因频率为0.00042。已知SYTL4基因可直接与RAB家族的几个成员相互作用，例如自闭症谱系障碍基因RAB27A，RAB27B，RAB8A和RAB3A。 SYTL4基因还直接与三个已知的自闭症基因相互作用：STX1A，SNAP25和STXBP1。通过基于文献的分析方法，我们在总共298个与小鼠Sytl4相关/预测的microRNA相互作用中，鉴定了具有高预测能力的五个（60％）自闭症相关血清microRNA（miR）中的三个。 13种miR中有5种（38％）在ASD个体的血清中差异表达，据预测与小鼠等效Sytl 4基因相互作用。 TMEM187基因与SYTL4类似，是一种蛋白质编码基因，属于在其内含子或外显子中带有microRNA基因的一组基因。在我们的患者中，TMEM187中新的Q236H氨基酸变体位于蛋白质的末端区域附近，该区域由多个序列比对和隐藏的马尔可夫模型表示，从而阻止了对该变异区域的比较结构分析。与SYTL4一样，TMEM187基因在大脑中表达并与四个已知的ASD基因HCFC1相互作用。 TMLHE; MECP2;和GPHN。 TMM187与MECP2相关联，MECP2是大脑结构和大小的众所周知的决定因素，并且是众所周知的自闭症基因。 TMEM基因家族的其他成员TMEM132E和TMEM132D基因分别与躁郁症和恐慌症相关，而TMEM231是已知的自闭症综合症基因。在一起，TMEM187和SYTL4基因直接与公认的重要ASD基因相互作用，并且它们的mRNA在神经系统的细胞外囊泡中发现，并刺激靶细胞转化为活性蛋白。我们的证据表明，这两个基因都应被视为自闭症的候选基因。必须进行其他生物学测试，以进一步确定自闭症的原因中这些基因变异的致病性。

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